PDF Inflammation Oxidative Stress and Cancer Dietary Approaches for Cancer Prevention 1st Edition Ah-Ng Tony Kong download

Download the full version of the ebook at ebookfinal.
com
Inflammation Oxidative Stress and Cancer Dietary

Approaches for Cancer Prevention 1st Edition Ah-Ng
Tony Kong
https://ebookfinal.com/download/inflammation-oxidative-
stress-and-cancer-dietary-approaches-for-cancer-
prevention-1st-edition-ah-ng-tony-kong/
OR CLICK BUTTON
DOWNLOAD EBOOK
Download more ebook instantly today at https://ebookfinal.com

Instant digital products (PDF, ePub, MOBI) available
Download now and explore formats that suit you...
Prevention of Cancer The Biology of Cancer 1st Edition

Robert G. Mckinnell
https://ebookfinal.com/download/prevention-of-cancer-the-biology-of-
cancer-1st-edition-robert-g-mckinnell/
ebookfinal.com
Skin Cancer Prevention 1st Edition Ringborg Ulrik
https://ebookfinal.com/download/skin-cancer-prevention-1st-edition-
ringborg-ulrik/
ebookfinal.com
Nutraceuticals in Health and Disease Prevention Oxidative

Stress and Disease 1st Edition Klaus Kramer
https://ebookfinal.com/download/nutraceuticals-in-health-and-disease-
prevention-oxidative-stress-and-disease-1st-edition-klaus-kramer/
ebookfinal.com
Epigenetics of Cancer Prevention 1st Edition Anupam

Bishayee
https://ebookfinal.com/download/epigenetics-of-cancer-prevention-1st-
edition-anupam-bishayee/
ebookfinal.com
ESMO Handbook of Cancer Prevention 1st Edition Dirk
Schrijvers
https://ebookfinal.com/download/esmo-handbook-of-cancer-
prevention-1st-edition-dirk-schrijvers/
ebookfinal.com
Hypermodels in Mathematical Finance 1st Edition Siu-Ah Ng
https://ebookfinal.com/download/hypermodels-in-mathematical-
finance-1st-edition-siu-ah-ng/
ebookfinal.com
Lung Cancer Prevention Management and Emerging Therapies

1st Edition Alejandro Corvalan
https://ebookfinal.com/download/lung-cancer-prevention-management-and-
emerging-therapies-1st-edition-alejandro-corvalan/
ebookfinal.com
Inflammation and Cancer Methods and Protocols Volume 2

Molecular Analysis and Pathways 1st Edition Yusuke Hiraku
https://ebookfinal.com/download/inflammation-and-cancer-methods-and-
protocols-volume-2-molecular-analysis-and-pathways-1st-edition-yusuke-
hiraku-2/
ebookfinal.com
Inflammation and Cancer Methods and Protocols Volume 2

Molecular Analysis and Pathways 1st Edition Yusuke Hiraku
https://ebookfinal.com/download/inflammation-and-cancer-methods-and-
protocols-volume-2-molecular-analysis-and-pathways-1st-edition-yusuke-
hiraku/
ebookfinal.com
Inflammation, Oxidative
Stress, and Cancer
Dietary Approaches for
Cancer Prevention
Inflammation, Oxidative
Stress, and Cancer
Dietary Approaches for
Cancer Prevention
Edited by
Ah-Ng Tony Kong
Boca Raton London New York
CRC Press is an imprint of the

Taylor & Francis Group, an informa business
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2014 by Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works

Version Date: 20130208
International Standard Book Number-13: 978-1-4665-0371-7 (eBook - PDF)
This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to
publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials
or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material repro-
duced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any
copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any
form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming,
and recording, or in any information storage or retrieval system, without written permission from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copy-
right.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400.
CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been
granted a photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identifica-
tion and explanation without intent to infringe.
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com
and the CRC Press Web site at

http://www.crcpress.com
Dedication
For my father, Kong Yuk-Ming, and my mother,

Lai Lang-Kiew, for their love and support
My teachers and mentors for their guidance, mentorship, and friendship
My wife, Carolyn, and my children, Emily and Andrew,
for their love, support, and encouragement
Contents
Preface...............................................................................................................................................xi
Acknowledgments........................................................................................................................... xiii
Editor................................................................................................................................................ xv
Contributors....................................................................................................................................xvii
Section I Inflammation, Oxidative Stress, Nutritional

Phytochemicals, and Cancer
Chapter 1 Overview on Oxidative Stress, Inflammation, Cancer Initiation/Progression,

and How to Prevent Carcinogenesis/Cancer.................................................................3
Jong Hun Lee and Ah-Ng Tony Kong
Chapter 2 Overview of Obesity, Inflammation, and Cancer........................................................ 21

Ximena Paredes-Gonzalez, Tin Oo Khor, Limin Shu, Constance Lay-Lay Saw,
and Ah-Ng Tony Kong
Chapter 3 Inflammation-Induced Esophageal and Colon Adenocarcinoma Formation in

Animal Models: Mechanisms of Carcinogenesis and Prevention.............................. 41
Chung S. Yang, Xiaoxin Chen, and Guang-Yu Yang
Chapter 4 Overview of Common Dietary Phytochemicals Possessing Antioxidant

Properties through Nrf2.............................................................................................. 55
Limin Shu, Chengyue Zhang, and Ah-Ng Tony Kong
Section II
Signal Transduction, Molecular Targets, and
Biomarkers of Dietary Cancer-Preventive
Phytochemicals
Chapter 5 Signal Transduction and Molecular Targets of Dietary Cancer-Preventive

Phytochemicals........................................................................................................... 81
Ann M. Bode and Zigang Dong
Chapter 6 Biomarkers for Diet in Cancer Prevention Studies................................................... 107

Zheng-Yuan Su, Limin Shu, and Ah-Ng Tony Kong
vii
viii Contents
Section III
In Vivo Absorption and Pharmacokinetics of
Nutritional Phytochemicals
Chapter 7 Metabolism and Transport of Anticancer and Anti-Inflammatory

Phytochemicals across the Gastrointestinal Tract.................................................... 135
Yong Ma and Ming Hu
Chapter 8 Pharmacokinetics of Dietary Isothiocyanates and Flavonoids................................. 171

Yoshihiko Ito, Shizuo Yamada, and Marilyn E. Morris
Section IV
Vitamins A, D, and E Cancer Prevention and
Clinical Perspective
Chapter 9 Retinoic Acid Signaling in Hematopoiesis and Immune Functions, and Options
for Chemoprevention................................................................................................. 185
Rodica P. Bunaciu and Andrew Yen
Chapter 10 Vitamin D and Inflammation in Cancer: Emerging Concepts..................................205

Katrina M. Simmons, Wei-Lin W. Wang, Martin P. R. Tenniswood, and
JoEllen Welsh
Chapter 11 Vitamin E Family of Compounds and Cancer Prevention........................................ 221

Kimberly Kline, Weiping Yu, Richa Tiwary, and Bob G. Sanders
Chapter 12 The Protective Role of Vitamin E in Inflammation and Cancer............................... 247

Amanda K. Smolarek and Nanjoo Suh
Chapter 13 Vitamin D and Cancer: Research Update and Clinical Recommendations............. 265
Kathleen M. Wesa and Barrie R. Cassileth
Section V Omega-3 and Omega-6 Fatty Acids
Chapter 14 Plant and Marine Sources of Omega-3 Polyunsaturated Fatty Acids,

Inflammation, and Cancer Prevention....................................................................... 281
Julie K. Mason, Ashleigh K. A. Wiggins, and Lilian U. Thompson
Chapter 15 Polyunsaturated Fatty Acids and Cancer Prevention................................................ 299

Janel Suburu and Yong Q. Chen
Contents ix
Chapter 16 Anti-Inflammatory and Proresolving Effects of Docosahexaenoic Acid:

Implications for Its Chemopreventive Potential........................................................ 311
Young-Joon Surh, Na-Young Song, Ha-Na Lee, and Hye-Kyung Na
Section VI Flavonoids and Polyphenols
Chapter 17 Green Tea and Cancer Prevention............................................................................. 331

Naghma Khan and Hasan Mukhtar
Chapter 18 Curcumin from Turmeric Spice, Anti-Inflammatory and Antioxidant

Phytochemical, and Cancer Prevention..................................................................... 343
Tin Oo Khor and Ah-Ng Tony Kong
Chapter 19 Flavonoids: Impact on Prostate Cancer and Breast Cancer...................................... 355

James Cardelli, David Coleman, and Katherine D. Crew
Chapter 20 Cancer Prevention by Isoflavone............................................................................... 387

Yiwei Li, Dejuan Kong, Aamir Ahmad, Bin Bao, and Fazlul H. Sarkar
Chapter 21 Anti-Inflammatory Efficacy of Silibinin: Role in Cancer Chemoprevention........... 401

Alpna Tyagi, Gagan Deep, and Rajesh Agarwal
Chapter 22 Cancer Prevention by Antioxidant Compounds from Berries.................................. 419

Noah P. Zimmerman, Dan Peiffer, and Gary D. Stoner
Section VII
Garlic Organosulfur Compounds and
Crucifer Glucusinolates
Chapter 23 Garlic and Cancer Prevention................................................................................... 435

Chi Chen
Chapter 24 Molecular Mechanisms of Cancer Chemoprevention with Benzyl Isothiocyanate..... 447

Anuradha Sehrawat and Shivendra V. Singh
Chapter 25 Suppression of Prostate Carcinogenesis by Dietary Isothiocyanates........................ 463

Young-Sam Keum
x Contents
Section VIII
Selenium, Herbal Medicines, Alpha Lipoic
Acid, and Cancer Prevention
Chapter 26 Cancer Prevention with Selenium: Costly Lessons and Difficult but Bright
Future Prospects........................................................................................................ 477
Junxuan Lü, Cheng Jiang, and Jinhui Zhang
Chapter 27 Chemoprevention of Lung Cancer by Ginseng......................................................... 495

Michael S. You, Lucina C. Rouggly, Ming Hu, Zhen Yang, Ming You, and Yian Wang
Chapter 28 Anti-Inflammatory Botanical Dietary Supplements for Women’s Health:

Role in Breast Cancer Prevention?............................................................................ 529
Birgit M. Dietz and Judy L. Bolton
Chapter 29 PHY906, a Cancer Adjuvant Therapy, Differentially Affects Inflammation of

Different Tissues....................................................................................................... 549
Wing Lam, Scott Bussom, Zaoli Jiang, Wei Zhang, Fulan Guan,
Shwu-Huey Liu, and Yung-Chi Cheng
Chapter 30 Lipoic Acid in the Prevention and Treatment of Inflammatory Disease and
Cancer....................................................................................................................... 563
Kate Petersen Shay, Regis F. Moreau, and Tory M. Hagen
Section IX Epigenetics and Chronic Inflammation
Chapter 31 Epigenetic Modifications by Dietary Phytochemicals in Cancer Prevention........... 577

Tabitha M. Hardy and Trygve O. Tollefsbol
Chapter 32 Nutritional Phytochemicals and the Management of Chronic Inflammation........... 589

Laura Marler and John M. Pezzuto
Index...............................................................................................................................................607
Preface
The major impetus for this book stems from the recent explosion of research on nutritional/dietary
phytochemicals—investigating their mechanisms of signaling/gene expression and their impact
on diseases including cancer. The second impetus came from participating in a symposium titled
“Diet, Inflammation and Cancer” for the American Institute Cancer Research (AICR) Annual
Research Conference on Food, Nutrition, Physical Activity and Cancer, October 21 and 22, 2010, in
Washington, DC, which triggered a lot of discussion.
Increasing scientific evidence suggests that a majority of diseases including cancer are driven
by oxidative stress and inflammation, attributed to environmental factors (viruses, carcinogens,
among others). These factors impinge on genetic materials, driving either genetic mutations and/or
epigenetically modifying expression of key regulatory genes (DNAs, RNAs, enzymes, receptors,
and cofactors, among others). These genetics/epigenetics events can occur as early as during gesta-
tional fetal development. The major questions remain as to how dietary phytochemical factors can
biochemically interact with such genetic/epigenetic events.
The main purpose of this book was to assemble a group of internationally well-recognized scien-
tific experts to examine and summarize the latest developments on the various dietary phytochemi-
cals. As a result, this book is divided into nine subsections, beginning with the basic mechanisms of
inflammation/oxidative stress–driven cancer initiation and development. This is followed by cellular
signal transduction, molecular targets and biomarkers of dietary cancer-preventive phytochemicals,
and their potential challenges with in vivo absorption and pharmacokinetics of these phytochemi-
cals. Then the various classes/groups of phytochemicals are examined. These include vitamins A,
D, and E; omega-3 and omega-6 fatty acids; flavonoids and polyphenols; garlic organosulfur com-
pounds and cruciferous glucusinolates; and selenium, traditional Chinese herbal medicines, and
alpha lipoic acid. The last section covers the latest developments in phyto-epigenomics and some
future perspective on the development of phytochemicals in disease prevention and treatment.
The intended audience includes graduate students, postdoctoral fellows, and scientists working
in the areas of nutrition, dietary phytochemicals, inflammation, oxidative stress, antioxidants in
general, and cancer more specifically. Furthermore, the general public will benefit from the great
overview, comprehensive analysis, and distillation of concepts discussed in this book.
xi
Acknowledgments
I am deeply indebted to the contributing authors who are passionate and have done so much to
advance the science of nutritional dietary phytochemicals and cancer chemoprevention as high-
lighted in the respective chapters of this book. I thank Ira Wolinsky who first contacted me regard-
ing the idea of putting this book together. Several individuals at CRC Press–Taylor & Francis
Group deserve special recognition for their efforts; Randy Brehm, Senior Editor, Chemical and
Life Sciences Group, Taylor & Francis Group, who helped to work on the contents; Kari Budyk,
Senior Project Coordinator, Editorial Project Development, CRC Press–Taylor & Francis Group,
who helped to facilitate and coordinate all the chapters; Joette Lynch, Project Editor, Production
Department, CRC Press–Taylor & Francis Group; and Amor Nanas, Manila Typesetting Company
(MTC), who played a key role in the producing of this book. Last but not least, I am deeply indebted
to my current and former laboratory members, many of whom are authors or coauthors in this book,
and to Hui Pung and Douglas Pung who helped coordinate and manage the book, without whose
help the completion of this book would not have been possible.
xiii
Editor
Ah-Ng “Tony” Kong, PhD, is a distinguished professor (PII), Glaxo Endowed Chair Professor of
Pharmaceutics, and director of the Graduate Program in Pharmaceutical Sciences at Rutgers, the
State University of New Jersey. He is also the director for the Center for Pharmacogenetics and
Pharmacogenomics at Rutgers University. Professor Kong earned his BS in pharmacy from the
University of Alberta, Canada; his PhD in pharmacokinetics and pharmacodynamics from the State
University of New York at Buffalo; and his postdoctoral training in molecular genetics and cellular
signaling at the National Institutes of Health (NIH). He is a fellow of the American Association of
Pharmaceutical Scientists. He was on the faculty of Thomas Jefferson University Medical School
and the University of Illinois at Chicago before joining Rutgers in early 2001. Dr. Kong has served
on numerous NIH Study Section panels since 1999, and he has been continuously receiving funding
support from the NIH since 1993.
Dr. Kong has trained more than 40 postdoctoral fellows, visiting professors, and PhD students.
He has published more than 200 original research papers, review articles, and book chapters,
and has chaired and given presentations at many national and international symposia and confer-
ences. He is currently serving on the board of 15 international journals, including Pharmaceutical
Research; Carcinogenesis; Biopharmaceutics and Drug Disposition; Cancer Prevention Research
(AACR); Molecular Carcinogenesis; Life Sciences; Pharmacological Research; Journal of
Chinese Pharmaceutical Sciences; Oncology Letters; Archives of Pharmacal Research; Acta
Pharmacologica Sinica; Cell Biosciences; and Journal of Traditional and Complementary
Medicine. His research areas are dietary phytochemicals (signaling and gene expression, nutrige-
nomics, cancer chemoprevention); animal tumor models of the prostate, colon, and skin; epigenetics/
epigenomics; oxidative/redox/inflammatory stress response; Nrf2-mediated nuclear transactivation
and signaling; and pharmacokinetics and pharmacodynamics of phytochemicals.
You can visit his website at http://pharmacy.rutgers.edu/content/faculty_profile_116.
xv
Contributors
Rajesh Agarwal James Cardelli
Department of Pharmaceutical Sciences Division of Basic and Translational Research
Skaggs School of Pharmacy and Feist-Weiller Cancer Center
Pharmaceutical Sciences and
and Department of Microbiology
University of Colorado Cancer Center Louisiana State University Health Sciences
University of Colorado Denver Center
Denver, Colorado Shreveport, Louisiana
Aamir Ahmad Barrie R. Cassileth

Department of Pathology Integrative Medicine Service
Barbara Ann Karmanos Cancer Institute Memorial Sloan–Kettering Cancer Center
Wayne State University School of Medicine New York, New York
Detroit, Michigan
Chi Chen
Bin Bao Department of Food Science and Nutrition
Department of Pathology University of Minnesota
Barbara Ann Karmanos Cancer Institute St. Paul, Minnesota
Wayne State University School of Medicine
Detroit, Michigan Xiaoxin Chen
Julius L. Chambers Biomedical/Biotechnology
Ann M. Bode Research Institute
The Hormel Institute North Carolina Central University
University of Minnesota Durham, North Carolina
Austin, Minnesota
Yong Q. Chen
Judy L. Bolton Department of Cancer Biology
Department of Medicinal Chemistry and Wake Forest School of Medicine
Pharmacognosy Winston-Salem, North Carolina
University of Illinois at Chicago
National Institutes of Health (UIC/NIH) Center and
for Botanical Dietary Supplements Research
University of Illinois at Chicago State Key Laboratory of Food Science and
Chicago, Illinois Technology
School of Food Science and Technology
Rodica P. Bunaciu Jiangnan University
Department of Biomedical Sciences Wuxi, China
Cornell University
Yung-Chi Cheng
Ithaca, New York
Department of Pharmacology
Yale University School of Medicine
Scott Bussom
New Haven, Connecticut
Yale University School of Medicine
xvii
xviii Contributors
David Coleman Ming Hu

Department of Microbiology Department of Pharmacological and
Louisiana State University Health Sciences Pharmaceutical Science
Center College of Pharmacy
Shreveport, Louisiana University of Houston
Houston, Texas
Katherine D. Crew
Herber Irving Comprehensive Cancer Center Yoshihiko Ito
Columbia University Medical Center Department of Pharmacokinetics and
New York, New York Pharmacodynamics
School of Pharmaceutical Sciences
Gagan Deep University of Shizuoka
Department of Pharmaceutical Sciences Shizuoka, Japan
Skaggs School of Pharmacy and
Pharmaceutical Sciences Cheng Jiang
and Department of Biomedical Sciences
University of Colorado Cancer Center School of Pharmacy
University of Colorado Denver Texas Tech University Health Sciences Center
Denver, Colorado Amarillo, Texas
Birgit M. Dietz Zaoli Jiang

Department of Medicinal Chemistry and Department of Pharmacology
Pharmacognosy Yale University School of Medicine
University of Illinois at Chicago New Haven, Connecticut
National Institutes of Health (UIC/NIH) Center
for Botanical Dietary Supplements Research Young-Sam Keum
University of Illinois at Chicago Department of Biochemistry
Chicago, Illinois College of Pharmacy
Dongguk University
Zigang Dong Goyang, Republic of Korea
The Hormel Institute
University of Minnesota Naghma Khan
Austin, Minnesota Department of Dermatology
University of Wisconsin
Fulan Guan Madison, Wisconsin
Yale University School of Medicine Tin Oo Khor
New Haven, Connecticut Center for Cancer Prevention Research
and
Tory M. Hagen Department of Pharmaceutics
Linus Pauling Institute Ernest Mario School of Pharmacy
and Rutgers, State University of New Jersey
Department of Biochemistry and Biophysics Piscataway, New Jersey
Oregon State University
Corvallis, Oregon Kimberly Kline
Department of Nutritional Sciences
Tabitha M. Hardy University of Texas at Austin
Department of Biology Austin, Texas
University of Alabama at Birmingham
Birmingham, Alabama
Contributors xix
Ah-Ng Tony Kong Yong Ma

Center for Cancer Prevention Research Department of Pharmacological and
and Pharmaceutical Sciences
Department of Pharmaceutics College of Pharmacy
Ernest Mario School of Pharmacy University of Houston
Rutgers, State University of New Jersey Houston, Texas
Piscataway, New Jersey
Laura Marler
Dejuan Kong College of Pharmacy
Department of Pathology University of Hawaii at Hilo
Barbara Ann Karmanos Cancer Institute Hilo, Hawaii
Wayne State University School of Medicine
Detroit, Michigan Julie K. Mason
Department of Nutritional Sciences
Wing Lam Faculty of Medicine
Department of Pharmacology University of Toronto
Yale University School of Medicine Toronto, Ontario, Canada
Regis F. Moreau
Ha-Na Lee Department of Nutrition and Health Sciences
Tumor Microenvironment Global Core University of Nebraska
Research Center Lincoln, Nebraska
College of Pharmacy
Seoul National University Marilyn E. Morris
Seoul, South Korea Department of Pharmaceutical Sciences
School of Pharmacy and Pharmaceutical
Jong Hun Lee Sciences
Center for Cancer Prevention Research University at Buffalo
and State University of New York
Department of Pharmaceutics Buffalo, New York
Ernest Mario School of Pharmacy
Rutgers, State University of New Jersey Hasan Mukhtar
Piscataway, New Jersey Department of Dermatology
University of Wisconsin
Yiwei Li Madison, Wisconsin
Department of Pathology
Barbara Ann Karmanos Cancer Institute Hye-Kyung Na
Wayne State University School of Medicine Department of Food and Nutrition
Detroit, Michigan Sungshin Women’s University
Seoul, South Korea
Shwu-Huey Liu
PhytoCeutica Inc Ximena Paredes-Gonzalez
Branford, Connecticut Center for Cancer Prevention Research
and
Junxuan Lü Department of Pharmaceutics
Department of Biomedical Sciences Ernest Mario School of Pharmacy
School of Pharmacy Rutgers, State University of New Jersey
Texas Tech University Health Sciences Center Piscataway, New Jersey
Amarillo, Texas
xx Contributors
Dan Peiffer Limin Shu

Department of Medicine Center for Cancer Prevention Research
Division of Hematology and Oncology and
Medical College of Wisconsin Department of Pharmaceutics
Milwaukee, Wisconsin Ernest Mario School of Pharmacy
Rutgers, State University of New Jersey
John M. Pezzuto Piscataway, New Jersey
College of Pharmacy
University of Hawaii at Hilo Katrina M. Simmons
Hilo, Hawaii Department of Biomedical Sciences and Cancer
Research Center
Lucina C. Rouggly Environmental Health Sciences
Department of Surgery University at Albany
and Rensselaer, New York
Alvin J. Siteman Cancer Center
Washington University School of Medicine Shivendra V. Singh
St. Louis, Missouri Department of Pharmacology and Chemical
Biology
Bob G. Sanders and
Section of Molecular Genetics and University of Pittsburgh Cancer Institute
Microbiology University of Pittsburgh School of Medicine
University of Texas at Austin Pittsburgh, Pennsylvannia
Austin, Texas
Amanda K. Smolarek
Fazlul H. Sarkar Department of Chemical Biology
Departments of Pathology and Oncology Ernest Mario School of Pharmacy
Barbara Ann Karmanos Cancer Institute and
Wayne State University School of Medicine Joint Graduate Program in Toxicology
Detroit, Michigan Rutgers, State University of New Jersey
Constance Lay-Lay Saw
Center for Cancer Prevention Research Na-Young Song
and Tumor Microenvironment Global Core
Department of Pharmaceutics Research Center
Ernest Mario School of Pharmacy College of Pharmacy
Rutgers, State University of New Jersey Seoul National University
Piscataway, New Jersey Seoul, South Korea
Anuradha Sehrawat Gary D. Stoner

Department of Pharmacology and Chemical Department of Medicine
Biology Division of Hematology and Oncology
and Medical College of Wisconsin
University of Pittsburgh Cancer Institute Milwaukee, Wisconsin
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvannia Zheng-Yuan Su
Center for Cancer Prevention Research
Kate Petersen Shay and
Linus Pauling Institute Department of Pharmaceutics
Oregon State University Ernest Mario School of Pharmacy
Corvallis, Oregon Rutgers, State University of New Jersey
Contributors xxi
Janel Suburu Alpna Tyagi

Department of Cancer Biology Department of Pharmaceutical Sciences
Wake Forest School of Medicine Skaggs School of Pharmacy and
Winston-Salem, North Carolina Pharmaceutical Sciences
University of Colorado Denver
Nanjoo Suh Denver, Colorado
Department of Chemical Biology
Ernest Mario School of Pharmacy Wei-Lin W. Wang
and Department of Biomedical Sciences and Cancer
Joint Graduate Program in Toxicology Research Center
Rutgers, State University of New Jersey Environmental Health Sciences
Piscataway, New Jersey University at Albany
Rensselaer, New York
and
Yian Wang
The Cancer Institute of New Jersey
Department of Surgery and Alvin J. Siteman
New Brunswick, New Jersey
Cancer Center
Young-Joon Surh Washington University School of Medicine
Tumor Microenvironment Global Core St. Louis, Missouri
Research Center
College of Pharmacy JoEllen Welsh
Seoul National University Cancer Research Center and Department of
Seoul, South Korea Environmental Health Sciences
University at Albany
Martin P. R. Tenniswood Rensselaer, New York
Department of Biomedical Sciences and Cancer
Research Center Kathleen M. Wesa
Environmental Health Sciences Integrative Medicine Service
University at Albany Memorial Sloan–Kettering Cancer Center
Rensselaer, New York New York, New York
Lilian U. Thompson Ashleigh K. A. Wiggins

Department of Nutritional Sciences Department of Nutritional Sciences
Faculty of Medicine Faculty of Medicine
University of Toronto University of Toronto
Toronto, Ontario, Canada Toronto, Ontario, Canada
Richa Tiwary Shizuo Yamada

Section of Molecular Genetics and Microbiology Department of Pharmacokinetics and
University of Texas at Austin Pharmacodynamics
Austin, Texas School of Pharmaceutical Sciences
University of Shizuoka
Trygve O. Tollefsbol Shizuoka, Japan
Department of Biology
Center for Aging Chung S. Yang
Comprehensive Cancer Center Department of Chemical Biology
Nutrition Obesity Research Center and
and Center for Cancer Prevention Research
Comprehensive Diabetes Center Ernest Mario School of Pharmacy
University of Alabama at Birmingham Rutgers, State University of New Jersey
Birmingham, Alabama Piscataway, New Jersey
xxii Contributors
Guang-Yu Yang Weiping Yu

Department of Pathology Section of Molecular Genetics and Microbiology
Feinberg School of Medicine University of Texas at Austin
Northwestern University Austin, Texas
Chicago, Illinois
Chengyue Zhang
Zhen Yang Department of Pharmaceutics
Department of Pharmacological and School of Pharmacy
Pharmaceutical Science Rutgers, State University of New Jersey
College of Pharmacy Piscataway, New Jersey
University of Houston
Houston, Texas Jinhui Zhang
Department of Biomedical Sciences
Andrew Yen School of Pharmacy
Department of Biomedical Sciences Texas Tech University Health Sciences Center
Cornell University Amarillo, Texas
Ithaca, New York
Wei Zhang
Michael S. You Department of Pharmacology
Department of Surgery Yale University School of Medicine
and New Haven, Connecticut
Alvin J. Siteman Cancer Center
Washington University School of Medicine Noah P. Zimmerman
St. Louis, Missouri Department of Microbiology and Molecular
Genetics
Ming You Medical College of Wisconsin
Medical College of Wisconsin Cancer Center Milwaukee, Wisconsin
and
Department of Pharmacology and Toxicology
Medical College of Wisconsin
Milwaukee, Wisconsin
Section I
Inflammation, Oxidative Stress,
Nutritional Phytochemicals, and Cancer
1 Overview on Oxidative
Stress, Inflammation, Cancer
Initiation/Progression,
and How to Prevent
Carcinogenesis/Cancer
Jong Hun Lee and Ah-Ng Tony Kong
CONTENTS
1.1 Introduction............................................................................................................................... 3
1.2 Chemical Carcinogens and Their Metabolic Activation...........................................................5
1.2.1 Metabolic Conversion of Chemical Carcinogens..........................................................6
1.2.2 Classes of Carcinogenic Chemicals...............................................................................6
1.2.2.1 Polycyclic Aromatic Hydrocarbons................................................................6
1.2.2.2 Heterocyclic Aromatic Amines......................................................................7
1.2.2.3 N-Nitrosamines...............................................................................................7
1.3 ROS/Reactive Nitrogen Species................................................................................................ 7
1.3.1 Defenses against Oxidative Stress................................................................................. 8
1.3.2 Nrf2/Keap1 Complex.....................................................................................................8
1.3.3 Dietary Phytochemicals Targeting Nrf2/Keap1 Signaling............................................ 8
1.4 Inflammation........................................................................................................................... 12
1.4.1 Anti-Inflammatory Phytochemicals............................................................................ 12
1.5 Hormone-Related Cancers....................................................................................................... 13
1.6 Perspective and Conclusion..................................................................................................... 13
Acknowledgments............................................................................................................................. 14
References......................................................................................................................................... 14
1.1 INTRODUCTION
Cancer is one of the major causes of mortality in the United States and other developed countries
(WHO 2011; Xu 2010). In 1975, approximately 400 cases of age-adjusted cancer incidences per
100,000 people were reported in the United States. The rates of cancer incidence in the United
States per 100,000 people in 1985, 1995, and 2005 were approximately 450, 475, and 465, respec-
tively (Jemal et al. 2009). Although significant progress has been made in the diagnosis and treat-
ment of human cancers, these malignancies remain a significant threat to human health.
The causes of most human cancers are complex and remain largely unknown. Carcinogenesis is
an asymptomatic, long-term process, which typically takes several years to progress from initiation
to advanced stages. Cancer can also occur in almost every anatomic part of the body and can arise
from a variety of different causes.
3
4 Inflammation, Oxidative Stress, and Cancer
Epidemiological data show that nutritional factors contribute to an average human cancer mor-
tality rate of 35%. A broad range of substances, especially those found in processed foods, have
been found to increase the risk of carcinogenesis. On the other hand, epidemiological studies sug-
gest that increased consumption of fruits and vegetables reduces cancer risk at various sites in the
body (Doll and Peto 1981; Giovannucci 1999). Many laboratory studies have reported that numer-
ous natural compounds isolated from food and edible plants exert anticancer effects by modifying
cancer-related cellular signaling pathways (Knasmuller et al. 2009; Surh 2003; Thomasset et al.
2007).
Wattenberg’s classic theory of chemoprevention states that the administration of one or more
chemical compounds can prevent the occurrence of cancer (Wattenberg 1966). Accumulating data
demonstrating the effects of various dietary compounds on cancer prevention has modified the
concept of chemoprevention. Currently, chemoprevention should be defined as an effective cancer
preventive approach used to inhibit, retard, or reverse human carcinogenesis at early stages using
nontoxic nutrients, phytochemicals, and synthetic pharmacological agents (Knasmuller et al. 2009).
Increasing data from cancer epidemiology and experimental efforts supports the idea of chemopre-
vention as a promising new approach to prevent carcinogenesis. It is important to understand the
molecular mechanisms of carcinogenesis because knowledge of these mechanisms enables us to
identify novel agents for targeted cancer chemoprevention and effective routes of administration
and to assay the bioavailability of currently available compounds.
Carcinogenesis is a long-term and multistage process that normally develops over more than
10 years and typically consists of three stages, known as initiation, promotion, and progression
(Armitage 1985). In the initiation stage, initiators such as carcinogens and radiation either react
with DNA directly or interact with intracellular macromolecules to form reactive molecules
that cause DNA damage and promote the transformation of normal cell into precancerous cells
(initiated cells). Once cells have unrepaired DNA damage, they are susceptible to progress into
the promotion stage because any daughter cells derived from the damaged cells will inherit this
alteration. Epigenetic alterations, including DNA methylation and histone modifications, are
also important gene regulatory mechanisms, and they play essential roles both independently
and cooperatively in tumor initiation and progression (Li, Carroll, and Dahiya 2005). In the
promotion stage, the initiated cells develop into preneoplastic cells. Promoters interact with
their specific receptors on the cell surface to induce the proliferation of preneoplastic cells
through intracellular signaling pathways. During the progression stage, neoplastic transforma-
tion is advanced, and the growing tumors develop invasive and metastatic potential (Hanahan
and Weinberg 2000; Moolgavkar 1978; Wattenberg 1985). Because reactive oxygen species
(ROS) or electrophiles are believed to play a critical role in carcinogenesis, the nuclear factor
(NF) erythroid-2 (NF-E2)–related factor 2 (Nrf2) and antioxidant and detoxifying enzymes act-
ing downstream of Nrf2 have emerged as important and effective molecular targets for chemo-
prevention because they prevent the toxic effects of ROS and electrophiles (Arisawa et al. 2007;
Braun et al. 2002). Various targets for chemoprevention have also been identified at each stage
of carcinogenesis. It has been suggested that chemopreventive agents should be categorized into
two groups, blocking agents and suppressing agents (Wattenberg 1985). Figure 1.1 describes
the multistage carcinogenic model and the relevant chemoprevention strategies. Dietary phy-
tochemicals obtained from daily foods and edible plants have received significant attention as
emerging compounds for cancer prevention due to their relatively low toxicity, low cost, and ease
of administration.
In this chapter, we will cover the various endogenous and exogenous carcinogenic factors that
are currently known in the field of carcinogenesis. The relevant anticarcinogenic strategies and
treatments, especially as they relate to chemopreventive dietary phytochemicals, will also be
discussed.
Oxidative Stress, Cancer Initiation, and Preventing Cancer 5
Normal cell
Carcinogen/chronic inflammation/hormone
Initiation
Metabolic
Carcinogen activation Procarcinogen
Initiated cell
DNA damage/methylation Blocking agents

Promotion Curcumin
Indole-3-carbinol
Sulphoraphane
Flavonoids
Preneoplastic cell
Proliferation of mutated cell/ Suppressing agents

transformation of cell structure Curcumin
Progression EGCG
Genistein
Resveratrol
Neoplastic cell [6]-Ginerol
Uncontrolled proliferation/angiogenesis
Tumor growth/metastasis
FIGURE 1.1 Dietary agents relevant for multistage carcinogenesis. The onset of carcinogenesis results from
the interaction of exogenous/endogenous carcinogenic compounds with intracellular macromolecules in nor-
mal cells, either directly or after metabolic activation. This can cause DNA damage/methylation, which, if not
repaired, can result in genetic and other cellular damage. These damaged cells develop into preneoplastic cells
upon altered expression of oncogenes and tumor suppressor genes during the promotion stage, resulting in
modified cell structure and proliferation. Finally, preneoplastic cells progress to neoplastic cells. This cascade
of events offers various chemopreventive targets at every stage. Some chemopreventive phytochemicals block
the initiation of carcinogenesis through inhibition of procarcinogen metabolic activation or of interaction of
the carcinogen with cellular macromolecules. On the other hand, some agents suppress the malignant trans-
formation of initiated cells during either the promotion or the progression stage. Some chemopreventive agents
have both types of activity.
1.2 CHEMICAL CARCINOGENS AND THEIR METABOLIC ACTIVATION

Humans are exogenously exposed to various xenobiotic chemicals that possess carcinogenic or
mutagenic properties. Chemical carcinogens can be categorized into two groups: direct-acting car-
cinogens and chemicals requiring activation. Due to their electrophilic properties and biologically
and chemically reactive structures, direct-acting carcinogens can interact with nucleophilic centers
in nucleic acids and proteins. In contrast, the majority of chemical carcinogens are biologically or
chemically inert in the body. However, through metabolic activation, these procarcinogens can be
converted into intermediate carcinogens and ultimately into electrophilic carcinogens. Because this
conversion requires the participation of specific enzyme systems in various species and organs,
procarcinogens have organ specificity for conversion and a wide variety of activities in the target
organ (Williams 1977).
1.2.1 Metabolic Conversion of Chemical Carcinogens

Carcinogens or procarcinogens can be metabolized by a phase I system to form a series of metabo-
lites. Phase I enzymes, especially cytochrome p450s (CYPs) and drug-metabolizing enzyme (DME),
convert lipophilic procarcinogenic chemicals into electrophiles by oxidation, reduction, isomeriza-
tion, or hydration of chemicals. This conversion results in the interaction of the electrophiles with
intracellular macromolecules, such as DNA, RNA, and proteins (Shimada et al. 1996; Gonzalez
and Gelboin 1994). Although a small fraction of procarcinogens are metabolically activated, these
transformed products can act as carcinogens. Thus, compounds that can regulate either the tran-
scription level or the activity of CYP could act as carcinogens (Danielson 2002; Wogan et al. 2004).
As a result of a recent increase in attention to CYPs, a large amount of data have been accumulated
demonstrating that metabolites formed by phase I CYPs can sometimes be reactive and damage
DNA and other cellular biomolecules. The CYP family is one of the largest multigene families in
the human genome; the CYPs are remarkable proteins because of the diversity of reactions they are
involved in and the range of substrates they act upon (Maheo et al. 1997; Danielson 2002).
1.2.2 Classes of Carcinogenic Chemicals

Because of the concerns about human health risks, tremendous effort has been focused on identify-
ing potential DNA-damaging and carcinogenic chemicals in human consumables, including food.
Hazardous chemicals vary widely in their chemical structures, modes of action, sources, and the
organs they affect. They are classified, mainly based on their functional groups, into the follow-
ing classes: polycyclic aromatic hydrocarbons (PAHs), heterocyclic aromatic amines (HCAs), and
N-nitrosamines (NAs) (Skog, Johansson, and Jagerstad 1998; Guengerich 1992).
1.2.2.1 Polycyclic Aromatic Hydrocarbons
PAHs are chemically inert and hydrophobic. However, CYP enzymes, particularly CYP1A1, meta
bolically activate PAHs to form diol epoxides that bind covalently to cellular macromolecules includ-
ing DNA. These reactive metabolites cause mutations and/or errors in DNA replication and result
in the initiation of carcinogenesis (Phillips 1983). The primary source of PAHs is the incomplete
combustion of organic materials such as coal, petroleum, and cigarette smoke. Workers in heavily
contaminated industrial areas, such as coal-tar production plants, iron foundries, coke ovens, and
aluminum production plants, are exposed to PAHs. However, the most common sources of PAHs
for humans are consumption of food that is contaminated by PAH particles and smoking. Several
studies have been conducted to determine the levels of PAHs in human diets. Considerable levels of
PAHs were detected in many types of uncooked food. In addition, cooking processes can generate
PAHs in food (Gomaa et al. 1993; Phillips 1983, 1999; Meador et al. 1995).
Like most environmental carcinogens, once PAHs in the environment are deposited in plants or
other low-level food sources, they enter the food chain and become concentrated as they accumulate
at higher levels of the food chain (Meador et al. 1995). The generation of woodsmoke is an example
of incomplete combustion, and PAHs are generated in the smoking process used to enrich flavor.
In salmon, concentrations of five carcinogenic PAHs (benzo[a]pyrene (BaP), benz[a]anthracene,
benzo[b]fluoranthene, dibenz[a,h]anthracene, and indeno[1,2,3-cd]pyrene) reached levels of 16.0 ppb
(Gomaa et al. 1993). When meat is cooked in direct contact with an open flame, pyrolysis of the fats
in the meat generates PAHs. Even if the meat is not in direct contact, fat dripping onto the flame
or hot coals generates PAHs, which adhere to the outer crust of the meat. Using low-temperature
cooking can reduce dietary exposure to PAHs (Phillips 1983, 1999). One cigarette contains 10–50 ng
of BaP and 12–140 ng of benz[a]anthracene (Rustemeier et al. 2002). Certain types of PAHs, such
as BaP and 7,12-dimethylbenzanthracene (7,12-DMBA), have been used frequently to induce carci-
nogenesis in laboratory rodents (Wattenberg 1977).
Early in the 1980s, Wattenberg et al. reviewed several nonnutrient constituents of food, including
terpene, curcumin, flavones, and β-carotene, that protect against PAH-induced cancer formation in
rodent models (Wattenberg 1992). They found that organic isothiocyanates blocked the production
of PAH-induced tumors through the suppression of carcinogen activation by CYP and the induction
of phase II detoxifying enzymes such as glutathione transferases and nicotinamide adenine dinu-
cleotide phosphate NAD(P)H:quinone reductase (Zhang and Talalay 1994). It has been reported
that the diol epoxides are substrates for glutathione S-transferases (GSTs), which conjugate them to
glutathione (Jernstrom et al. 1996).
1.2.2.2 Heterocyclic Aromatic Amines

Since the Japanese scientist Takashi Sugimura discovered the mutagenicity of smoke from grilled
fish, approximately 20 different HCAs have been identified (Sugimura et al. 2004). In a model
system, a heated reaction of sugar and amino acids together with the major precursor creatine
or creatinine generated mutagenic HCAs such as 2-amino-3-methylimidazo[4,5-f]quinolone
(IQ), 2-amino-α-carboline (AαC), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
(Jagerstad et al. 1991). HCAs are metabolized mainly by CYP1A2 in rodents and humans via the
N-oxidation of the exocyclic primary amino group. The hydroxyamino group is subsequently cata-
lyzed by N(O)-acetyltransferases (NATs). N-acetoxy metabolites of HCAs are spontaneously con-
verted to arylnitrenium ions (R-NH+) and react with DNA to form adducts at the 8-position carbon
of the guanine base (Sugimura et al. 2004). Exposure of Fisher344 rats to PhIP, which is found in
cooked meat, causes cancer in the rat ventral prostate by lobe-specific infiltration of mast cells and
macrophages in response to PhIP (Nakai, Nelson, and De Marzo 2007).
Decreased consumption of fried meat, the reduction of frying temperature, and the usage of
antioxidant-rich oil during cooking are ways to reduce the production and consumption of HCAs because
HCA generation mainly depends on an increase in temperature and heating time and on dehydration
of the meat (Knize et al. 2002). Treatment with Brussels sprout extract reduces DNA damage in PhIP-
treated human lymphocytes by inhibiting sulfotransferase 1A1, which plays a key role in the activation
of PhIP (Hoelzl et al. 2008). Indole-3-carbinol, which is present in cruciferous vegetables, was shown
to suppress aberrant crypt foci (ACF) development caused by PhIP in IQ-treated rats (Dashwood 2002).
1.2.2.3 N-Nitrosamines
NAs are nitroso derivatives of secondary amines that occur in the human diet and environment
and can be formed endogenously in the human digestive tract (Tricker and Preussmann 1991). NAs
are metabolized by CYP2E1, which hydroxylates the α carbon atom to nitroso groups. The unsta-
ble intermediate produced easily releases a nitrogen molecule, leading to a reactive species. This
highly reactive electrophile can contribute to the formation of protein and DNA adducts (Nouso,
Thorgeirsson, and Battula 1992). The regulation of α-hyroxyalkylnitrosamine formation by CYP
has been reported in animals and humans (Guengerich 1992; Yang et al. 1990).
Along with lifestyle modifications, such as reducing dietary exposure to NAs by decreasing con-
sumption of cured meat that contains large amounts of NAs, the consumption of dietary polyphenol
is another potential approach to reduce the risk of NA exposure. Various Chinese teas inhibit the
endogenous formation of N-nitrosomorpholine in vitro and in vivo (Wu et al. 1993). The effect of
vitamin A on 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a confirmed carcinogen in
humans, was studied in a model of induced genotoxic damage in the rat liver. Compared with the
group fed with a vitamin A–deficient diet, the vitamin A–supplemented group showed a significant
decrease in the number of micronuclei. In isolated hepatocytes from vitamin A–fed rats, NNK was
metabolized much less effectively, compared with cells from rats fed with a vitamin-deficient diet
(Alaoui-Jamali, Rossignol, and Castonguay 1991).
1.3 ROS/REACTIVE NITROGEN SPECIES

ROS are byproducts of the mitochondrial respiratory chain that is responsible for most of the oxygen
reduction and energy generation in cells; they are eliminated by protective mechanisms, including
antioxidants, in normal conditions. Under sustained environmental stress, prolonged production of

ROS may cause damages in cellular structure and induce somatic mutations and neoplastic trans-
formation. Under hypoxic conditions, the mitochondrial respiratory chain also produces nitric oxide
(NO), which can generate reactive nitrogen species (RNS). Thus, oxidative stress is an imbalance
between the generation of ROS/RNS and the antioxidative stress defense systems (Poyton, Ball,
and Castello 2009; Reuter et al. 2010; Valko et al. 2007). A large amount of evidence has demon-
strated that oxidative stress contributes to most human diseases, including various types of cancers,
Alzheimer’s disease (AD), and Parkinson’s disease (PD) (Emerit, Edeas, and Bricaire 2004; Cataldi
2010).
1.3.1 Defenses against Oxidative Stress

As introduced in Section 1.2, phase I enzymes, including CYP, are involved in the metabolic activa-
tion of procarcinogens. Phase II enzymes, also known as “detoxifying enzymes,” can facilitate cellular
protection. The induction of phase II detoxifying and antioxidant enzymes, such as GST, NAD(P)H
quinone oxidoreductase 1 (NQO1), Uridine 5′-diphospho (UDP)-glucuronosyltransferase (UGT),
and hemeoxigenase-1 (HO-1), has been proposed as an effective cytoprotective approach against
oxidative stress, as well as the neoplastic process of carcinogenesis (Jeong, Jun, and Kong 2006).
GST, UGT, and sulfotransferase modify electrophilic xenobiotics or metabolites of phase I enzymes
with endogenous groups (glutathione, glucuronide, and sulfate, respectively) to reduce their toxic-
ity and reactivity by increasing the solubility of these conjugates and excreting them. In addition
to conjugating electrophiles and metabolites, phase II enzymes act as antioxidants by generating
endogenous molecules such as glutathione (Jeong, Jun, and Kong 2006; Maheo et al. 1997; Paul et
al. 2005; Pool-Zobel, Veeriah, and Bohmer 2005; Talalay 2000; Zhao et al. 2001).
1.3.2 Nrf2/Keap1 Complex
The expression of phase II enzymes at the transcriptional level is stimulated through antioxidant
response elements (AREs), which are found in the regulatory regions of most phase II and antioxi-
dant genes. Nrf2, a member of the NF-E2 family of nuclear basic leucine zipper (bZIP) transcrip-
tion factors, and Kelch-like ECH-associated protein 1 (Keap1), a cytoplasmic protein homologous
to the Drosophila actin-binding protein Kelch, play key roles in regulating ARE-mediated gene
expression (Ramos-Gomez et al. 2001; Surh 2003). In both wild-type and heterozygous Nrf2 mutant
mice, phenolic antioxidants markedly induced the expression of phase II enzymes such as GST and
NQO1. However, in homozygous null mice, the expression of these enzymes was largely abolished.
This result confirmed that Nrf2 plays an essential role in the transcriptional induction of phase II
enzymes (Itoh et al. 1997). Wakabayashi et al. (2003) showed that homozygous Keap1 mutant mice
died postnatally due to hyperkeratosis in their esophagus and forestomach, which led to starvation.
This phenomenon was also observed in vitro in squamous cell epithelia. They also found that Nrf2
accumulates in the nuclei of homozygous Keap1 mutant cells and that constitutive expression of
Nrf2 target genes was markedly increased. These experiments demonstrated that Keap1 acts as an
upstream regulator of Nrf2 in response to oxidative and xenobiotic stress (Wakabayashi et al. 2003).
1.3.3 Dietary Phytochemicals Targeting Nrf2/Keap1 Signaling

Isothiocyanates, including sulforaphane (SFN) and phenethyl isothiocyanate (PEITC), are present
in cruciferous vegetables such as broccoli, watercress, and cabbage. These sulfur-containing com-
pounds play a critical role in Nrf2/Keap1 signaling. Lin et al. (2008) compared the expression levels
of various inflammatory markers to determine the effect of SFN on lipopolysaccharide (LPS)-
induced macrophages. Pretreatment of Nrf2+/+ macrophages with SFN inhibited LPS-induced mes-
senger RNA (mRNA) expression, protein expression, and the production of tumor necrosis factor
(TNF)-alpha, interleukin (IL)-1β, cyclooxygenase-2 (COX-2), and inducible NO synthase (iNOS),

whereas an attenuated anti-inflammatory response was observed in SFN-treated Nrf2–/– macro-
phages. The expression of HO-1, a detoxifying enzyme downstream of Nrf2, was significantly
increased in LPS-induced Nrf2+/+ macrophages by SFN. This result led to the conclusion that SFN
exerts its anti-inflammatory activity primarily via the activation of Nrf2 in macrophages (Lin et
al. 2008). Another isothiocyanate, PEITC, had a synergistic effect with curcumin in xenografted
human PC-3 prostate cells. Combined intraperitoneal administration of PEITC and curcumin
led to stronger growth-inhibitory effects, compared to PEITC and curcumin treatment alone.
Immunohistochemistry and western blot analysis revealed that inhibition of the Akt and NF-κB sig-
naling pathways contribute to the inhibition of cell proliferation and induction of apoptosis observed
upon coadministration of PEITC and curcumin (Khor et al. 2006).
Resveratrol (3,4′,5-trihydroxystilbene), a phytoalexin found in the skin and seeds of grapes, has
been reported to possess anti-inflammatory, anticarcinogenic, and antioxidant activities. Resveratrol
treatment induces HO-1 expression through the transcriptional activation of Nrf2. In addition, PC12
cells treated with resveratrol exhibited transient activation of Akt/protein kinase B and Extracellular
signal-regulated kinase (ERK1/2) (Chen et al. 2005). Table 1.1 lists various phytochemicals that
regulate the Nrf2 pathway and inflammation.
TABLE 1.1
Chemopreventive Compounds Found in the Diet
Compound Plant Source Effects/Molecular Mechanisms In Vivo Test
Caffeic acid/ Coffee Caffeic acid–modulated ceramide-induced signal
chlorogenic acid transduction pathway and NF-κB activation via
antioxidant and non-antioxidant mechanisms in
U937 cells (Nardini et al. 2001).
Pretreatment of JB6 cells with chlorogenic acid
blocked UVB- or 12-O-tetradecanoylphorbol-
13-acetate (TPA)-induced transactivation of
AP-1 and NF-κB over the same dose range.
Chlorogenic acid decreased the phosphorylation
of MAPK was induced by UV-B/TPA (Feng et
al. 2005).
Curcumin Curcuma Curcumin inhibited NF-κB activation by Dietary curcumin caused an
longa repressing the degradation of its inhibitory unit, increase in Nrf2 protein
IκBα, which hampers subsequent nuclear levels and enhanced its
translocation of active NF-κB, leading to nuclear translocation in the
inhibition of the expression of COX-2 and iNOS livers and lungs of
(Surh et al. 2001). BaP-treated mice (Garg,
Curcumin treatment led to decreased expression Gupta, and Maru 2008).
of NF-κB and COX-2. The tobacco-specific
nitrosamine (NNK) is one of the carcinogenic
components of smokeless tobacco extract. It was
found that curcumin pretreatment abrogates
NNK-induced activation of NF-κB and COX-2
expression (Sharma et al. 2006).
Curcumin stimulates HO-1 and glutathione
S-transferase pi (GSTP1) gene activity by
causing dissociation of Nrf2 from Keap1,
leading to increased Nrf2 binding to the resident
HO-1 AREs in HepG2 cells (Balogun et al.
2003; Nishinaka et al. 2007).
(continued)
TABLE 1.1 (Continued)

3,3′-diindolylmethane Cruciferous DIM stimulated BRCA1 (breast cancer1)
(DIM) vegetables signaling by activating the antioxidant
transcription factor Nrf2 in human mammary
epithelial cells (Fan et al. 2009).
(-)-Epogallocatechin Green tea EGCG dose-dependently inhibited cell growth Nrf2-dependent gene
gallate (EGCG) and induced apoptosis in A431 cells (Ahmad, expression was
Gupta, and Mukhtar 2000). downregulated (3-fold to
EGCG inhibited COX-2 and iNOS expression by 35-fold) after combined
blocking improper activation of NF-κB (Surh et administration of EGCG
al. 2001). (100 mg/kg) and SFN (45
EGCG increased the nuclear accumulation, ARE mg/kg) to Nrf2 knockout
binding, and transcriptional activity of Nrf2 via mice (Nair et al. 2010).
activation of PI3K and ERK in MCF10A cells
(Na et al. 2008). The activation of AP-1 was
attenuated by combined treatment with SFN and
EGCG in PC-3 cells (Nair et al. 2010).
EGCG abrogated p300-induced p65 acetylation
and suppressed TNF-α–induced NF-κB
activation, confirming that hyperacetylation is
critical for NF-κB translocation and activity
(Choi et al. 2009).
Genistein Soy The BTG3 tumor suppressor gene is Feeding with genistein-
epigenetically silenced in renal cell carcinoma enriched diets (2 g/kg) for
but was shown to be reactivated by genistein- more than 3 weeks
induced promoter demethylation and active significantly increased both
histone modification in HEK-293 cells (Majid et the hepatic mRNA levels
al. 2009). and the activity of NQO1
Genistein treatment increased the acetylation of (Wiegand et al. 2009).
histones 3, 4, and H3/K4 at the p21 and p16
transcription start sites in LNCaP cells (Majid et
al. 2008).
Lycopene Tomato Lycopene inhibited the inflammatory response of Lycopene caused DU145
RAW 264.7 cells to LPS through inhibition of cells to accumulate in the
ERK, p38, and the NF-κB pathway (Feng, Ling, G(0)/G(1) phase and to
and Duan 2010). undergo apoptosis in a
Activation of Nrf2 by apo-10′-lycopenoic acid, a dose-dependent manner in
metabolite of lycopene, induced the expression DU145 tumor xenografts in
of phase II detoxifying/antioxidant enzymes BALB/c male nude mice
including HO-1, NQO1, and GST in BEAS-2B (Tang et al. 2005).
cells (Lian and Wang 2008).
(continued)
TABLE 1.1 (Continued)

PEITC Cruciferous Combined treatment with PEITC and SFN A combination of curcumin
vegetables decreased the expression of inflammatory and PEITC significantly
markers, including TNF-α, IL-1, NO, and PGE2. reduced the growth of PC-3
The synergism was most likely due to the xenografts. PEITC inhibited
synergistic induction of phase II/antioxidant the Akt and NF-κB signaling
enzymes including HO-1 and NQO1 (Cheung, pathways, leading to
Khor, and Kong 2009). inhibition of proliferation
PEITC induced the expression of HO-1 and and induction of apoptosis
increased ARE activity. PEITC also increased the (Khor et al. 2006).
phosphorylation of ERK1/2 and JNK1/2 and Azoxymethane (AOM)/
caused the release of Nrf2 from sequestration by Dextran sulfate sodium
Keap1 and its subsequent translocation into the (DSS) mice fed a PEITC- or
nucleus in HepG2 cells (Xu et al. 2006). dopamine-beta-
monooxygenase (DBM)-
supplemented diet had lower
tumor incidences, lower
colon tumor multiplicities,
and smaller polyps, as
compared to mice fed with
the standard AIN-76A diet
(Cheung et al. 2010).
Resveratrol Grapes, wine Pretreatment with resveratrol attenuated hydrogen Resveratrol reduced lung
peroxide-induced cytotoxicity, DNA tissue neutrophilia to a
fragmentation, and intracellular accumulation of similar extent as treatment
ROS via inhibition of the NF-κB pathway in with budesonide in a rodent
PC12 cells (Jang and Surh 2001). model of LPS-induced
Resveratrol inhibited TNF-α-induced NF-κB airway inflammation
activation and inflammatory gene expression and (Birrell et al. 2005).
attenuated monocyte adhesion to HCAECs
(Csiszar et al. 2006).
The treatment of resveratrol caused the release of
cytosolic Nrf2, followed by the translocation of
Nrf2 into the nucleus, leading to the transcriptional
activation of NQO1 (Hsieh et al. 2006).
SFN Cruciferous SFN and PEITC inhibited NF-κB, as well as UV radiation–induced skin
vegetables expression of the NF-κB target genes VEGF, carcinogenesis was
cyclin D1, and Bcl-X(L); it also decreased substantially inhibited by
nuclear translocation of p65 in PC-3 cells (Xu et broccoli sprout extracts
al. 2005). containing SFN (Dinkova-
SFN reacts with the thiol groups of Keap1 to form Kostova et al. 2006).
thionoacyl adducts (Hong, Freeman, and Liebler SFN increased the
2005). expression of Nrf2-
regulated proteins that
directly detoxify exogenous
toxins/carcinogens or
endogenous ROS in Nrf2
knockout mice (Hu et al.
2006).
1.4 INFLAMMATION
The relationship between inflammation and cancer has been highlighted by cancer researchers as an
exciting, promising area for exploration that could help to solve this global health concern (Bartsch
and Nair 2006; Hussain, Hofseth, and Harris 2003). Approximately 18% of the 10 million new
global cases of cancer in 2000 were related to chronic inflammation that was induced by persistent
biological, chemical, and physical factors (Parkin 2001). If acute inflammation, the first defensive
attempt of our body, fails to remove exogenous stimuli or lasts too long, it can become chronic and
may serve as a cause of various diseases (Aggarwal et al. 2006). In chronic inflammation, activated
inflammatory/immune cells, such as eosinophiles, dendritic cells, leukocytes, macrophages, mast
cells, monocytes, natural killer cells, neutrophils, and phagocytes, release proinflammatory mole-
cules, including cytokines, chemokines, matrix-remodeling proteases, ROS, and RNS, to eliminate
pathogens and repair tissue damage. However, various proinflammatory cytokines, chemokines,
ROS, and RNS can cause genetic changes or epigenetic alterations, such as DNA methylation and
posttranslational modifications, in tumor suppressor genes (Hussain and Harris 2007).
Thus, due to the mechanistic relationship between cancer and inflammation, a better understand-
ing of the molecular mechanisms of chronic inflammation could expand the scope of cancer preven-
tion research. It has been reported that cytokines, NF-κB, iNOS, and COX2 play a pivotal role in
inducing cancer (Lu, Ouyang, and Huang 2006).
1.4.1 Anti-Inflammatory Phytochemicals
Epigallocatechin-3-gallate (EGCG) is the most abundant catechin in green tea. Due to its strong
antioxidant properties, EGCG is also one of the most widely studied polyphenolic compounds. In
human chondrocytes, EGCG inhibited the activation of NF-κB by suppressing the degradation of
IκBα in the cytoplasm, leading to reduced induction of iNOS and lower production of NO (Singh et
al. 2002). EGCG also inhibited IL-1β-induced NO and prostaglandin E2 (PGE2) production by reg-
ulating the expression and catalytic activity of iNOS and COX-2 (Ahmed et al. 2002). EGCG treat-
ment inhibited ultraviolet (UV)-B–induced mitogen-activated protein kinase (MAPK) and NF-κB
signaling in normal human epidermal keratinocytes in a dose-dependent manner (Afaq et al. 2003).
EGCG not only acts as an anti-inflammatory modulator via effects on the NF-κB pathway but also
regulates other anticancer effectors, including p53, Bcl-2, Bax, and the caspases. Lee et al. (2011)
treated HT-1080 cells with fluorescein isothiocyanate (FITC)–conjugated EGCG (FITC-EGCG).
The time-dependent internalization of FITC-EGCG into the cytosol of HT-1080 cells and its subse-
quent nuclear translocation were observed. The expression of p53, caspase-7, and caspase-9, as well
as the ratio of the Bax/Bcl-2 protein, increased significantly in the EGCG-treated group, suggest-
ing that EGCG may interrupt exogenous signals that are directed toward cancer-related genes (Lee
et al. 2011). In fact, various inflammatory modulators are now believed to be connected to other
carcinogenic mechanisms, such as apoptosis and metastasis. Various dietary phytochemicals also
have multiple effects on these molecular targets. However, this review is focused on inflammation,
antioxidant/detoxifying enzymes, and epigenetic modification.
Curcumin is a bright yellow powder present in the rhizome of turmeric (Curcuma longa L.)
and is used as a food coloring and flavoring. Curcumin is extensively studied for its potential anti-
cancer activity. Chen and Tan (1998) reported that curcumin inhibits the MEKK1-jun N-terminal
kinase (JNK) pathway, suggesting a possible mechanism for the suppression of activator protein-1
(AP-1) and NF-κB signaling in various human cell lines. Oral administration of curcumin signifi-
cantly attenuated histological damage and caused substantial reductions in myeloperoxidase activ-
ity and TNF-α. Curcumin also reduced the colonic nitrite levels and downregulated the expression
of COX-2 and iNOS by decreasing p38 MAPK in a trinitrobenzenesulfonic acid–induced rat model
(Camacho-Barquero et al. 2007). In a phase II trial of curcumin in patients with advanced pancre-
atic cancer, conjugated forms of curcumin were detected at very low levels in blood vessels. Some
patients had tumor regression or stable disease without observed toxicity. In blood mononuclear
cells from patients, curcumin decreased the expression of NF-κB, COX-2, and phosphorylated sig-
nal transducer and activator of transcription 3 (STAT3). This result demonstrated that oral admin-
istration of curcumin is well tolerated and, despite its limited absorption, has biological effects in
some pancreatic cancer patients (Dhillon et al. 2008). As shown above, each phytochemical does
not affect only one specific molecular target. Although the same compound was used for treat-
ment in each case, numerous linked signaling pathways function in concert, thus leading to various
results depending on cell type, dosage, and method of treatment. Various phytochemicals with in
vitro and in vivo anti-inflammatory effects are summarized in Table 1.1.
In addition to Nrf2/Keap1, these compounds have multiple other biochemical targets.
Interestingly, anti-inflammatory compounds also have significant effects on Nrf2 effects, which
suggests that their cytoprotective mechanism is closely related to their anti-inflammatory reactions.
1.5 HORMONE-RELATED CANCERS
Hormone-related cancers, such as breast, uterine, ovary, prostate, thyroid, and osteosarcoma, are
thought to share a unique mechanism of carcinogenesis. Both endogenous and exogenous hormones
drive cell proliferation and increase the number of cell divisions. This proliferation leads to the
increased probability of random genetic errors (Henderson et al. 1982; Henderson and Feigelson
2000). Random errors in DNA occur during cell division, and these mutations can cause a malig-
nant phenotype. The hormonal stimulus for cell division continues in the latter stages of promo-
tion and progression (Henderson et al. 1982; Ross et al. 1998; Henderson, Ross, and Pike 1991).
Catechol estrogens (CEs) are the major metabolites of aromatase and estrone (Zhu et al. 1998). If
these metabolites are oxidized to the electrophilic CE-quinone (CE-Q), they may react with DNA.
In particular, the carcinogenic 4-hydroxyestrone (estradiol) [4-OHE1 (E2)] is oxidized to estrone
(estradiol)-3,4-quinone [E1 (E2)-3,4-Q], which can react with DNA to form depurinating adducts
(Cavalieri et al. 1997). The release of these adducts generates error-prone apurinic sites that may
lead to cancer-initiating mutations. Finally, these mutations can initiate breast, prostate, and other
types of cancer (Cavalieri et al. 2006). 17β-Estradiol is regarded as an endogenous tumor promoter,
and it interacts with the estrogen receptors ERα and ERβ to stimulate cell growth and increase the
risk of hormone-dependent tumors (Yager and Davidson 2006).
Modifying the endogenous levels of circulating hormones is a key therapeutic way to reduce the
incidence of hormone-dependent cancers. However, in the absence of changes in exercise, diet, and
smoking, the endogenous levels of a hormone are not easy to control. Using antihormonal therapies
such as tamoxifen to block the hormonal stimuli that cause DNA damage can lead to a reduction in
hormone-dependent cancers. It has been reported that tamoxifen reduces the risk of invasive breast
cancer by 49% (P < .00001) and noninvasive breast cancer by 50% (P < .002) (Fisher et al. 1998).
However, while tamoxifen reduces the risk of certain breast cancers and bone fractures, it increases
the risk of endometrial cancer (Henderson and Feigelson 2000). Phytoestrogens such as lignans, iso-
flavones, and flavanones are plant-derived chemicals. Due to their structural homology with estro-
gens, phytoestrogens can mimic the effects of estrogen. Their estrogen-like activity may contribute
to the chemoprotective effects of phytoestrogens by lowering the levels of circulating precursors.
In addition, their antioxidant activity may prevent free-radical damage. However, the influence of
phytoestrogens on hormone-dependent tumors is still controversial (Rice and Whitehead 2006).
1.6 PERSPECTIVE AND CONCLUSION

An urban lifestyle increases the risks of exposure to various toxins, including environmental pol-
lutants, dietary mutagens, carcinogens, microorganisms, and solar radiation. Inflammation-induced
oxidative stress on cellular macromolecules may downregulate the expression of tumor suppressor
genes or lead to the transformation and activation of oncogenes (Coussens and Werb 2002; Shu et
al. 2010). Preclinical and clinical trials, as well as laboratory research, have provided evidence that
dietary phytochemicals have multiple chemopreventive effects during the initiation and progression
of cancer. In this chapter, we reviewed promising dietary phytochemicals that possess potential
chemopreventive effects on various carcinogenic factors, including inflammation, oxidative stress,
chemical carcinogens, and endogenous hormones.
Although the beneficial effects of dietary phytochemicals on human carcinogenesis have been
promising, effective, and safe, further studies on these natural dietary compounds will be required.
It is necessary to elucidate which molecular targets in the signaling pathways are affected by phyto
chemicals to find more effective and efficient chemoprevention solutions.
The relatively low toxicity, ease of access, and low cost of a diverse number of phytochemicals
encourage us to investigate their chemopreventive effects. Daily consumption of fresh vegetables
and fruits containing beneficial phytochemicals could be a “quiet but strong” defense system that
suppresses or prevents carcinogenesis.
ACKNOWLEDGMENTS
The authors’ work cited in this review article was supported in part by institutional funds and by
RO1-CA073674, RO1-CA094828, R01-CA118947, and R01-CA152826, which were awarded to Dr.
Ah-Ng Tony Kong by the National Institutes of Health (NIH).
REFERENCES
Afaq, F., V. M. Adhami, N. Ahmad, and H. Mukhtar. 2003. Inhibition of ultraviolet B-mediated activation of
nuclear factor kappa B in normal human epidermal keratinocytes by green tea Constituent (-)-epigallo-
catechin-3-gallate. Oncogene 22 (7):1035–1044.
Aggarwal, B. B., S. Shishodia, S. K. Sandur, M. K. Pandey, and G. Sethi. 2006. Inflammation and cancer: How
hot is the link? Biochemical Pharmacology 72 (11):1605–1621.
Ahmad, N., S. Gupta, and H. Mukhtar. 2000. Green tea polyphenol epigallocatechin-3-gallate differentially
modulates nuclear factor kappa B in cancer cells versus normal cells. Archives of Biochemistry and
Biophysics 376 (2):338–346.
Ahmed, S., A. Rahman, A. Hasnain, M. Lalonde, V. M. Goldberg, and T. M. Haqqi. 2002. Green tea polyphenol
epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and
nitric oxide synthase-2 in human chondrocytes. Free Radical Biology and Medicine 33 (8):1097–1105.
Alaoui-Jamali, M. A., G. Rossignol, and A. Castonguay. 1991. Protective effects of vitamin A against the geno-
toxicity of NNK, a nicotine-derived N-nitrosamine. Carcinogenesis 12 (3):379–384.
Arisawa, T., T. Tahara, T. Shibata, M. Nagasaka, M. Nakamura, Y. Kamiya, H. Fujita, S. Hasegawa, T. Takagi,
F. Y. Wang, I. Hirata, and H. Nakano. 2007. The relationship between Helicobacter pylori infection
and promoter polymorphism of the Nrf2 gene in chronic gastritis. International Journal of Molecular
Medicine 19 (1):143–148.
Armitage, P. 1985. Multistage models of carcinogenesis. Environmental Health Perspectives 63:195–201.
Balogun, E., M. Hoque, P. F. Gong, E. Killeen, C. J. Green, R. Foresti, J. Alam, and R. Motterlini. 2003.
Curcurnin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive
element. Biochemical Journal 371:887–895.
Bartsch, H., and J. Nair. 2006. Chronic inflammation and oxidative stress in the genesis and perpetuation of
cancer: role of lipid peroxidation, DNA damage, and repair. Langenbecks Arch Surg 391 (5):499–510.
Birrell, M. A., K. McCluskie, S. Wong, L. E. Donnelly, P. J. Barnes, and M. G. Belvisi. 2005. Resveratrol, an
extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators
through an NF-kappaB-independent mechanism. FASEB Journal 19 (7):840–841.
Braun, S., C. Hanselmann, M. G. Gassmann, U. auf dem Keller, C. Born-Berclaz, K. Chan, Y. W. Kan, and
S. Werner. 2002. Nrf2 transcription factor, a novel target of keratinocyte growth factor action which
regulates gene expression and inflammation in the healing skin wound. Molecular and Cell Biology 22
(15):5492–5505.
Camacho-Barquero, L., I. Villegas, J. M. Sanchez-Calvo, E. Talero, S. Sanchez-Fidalgo, V. Motilva, and C. A. de la
Lastra. 2007. Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and
NOS expression in chronic experimental colitis. International Immunopharmacology 7 (3):333–342.
Cataldi, A. 2010. Cell responses to oxidative stressors. Current Pharmaceutical Design 16 (12):1387–1395.
Cavalieri, E., D. Chakravarti, J. Guttenplan, E. Hart, J. Ingle, R. Jankowiak, P. Muti, E. Rogan, J. Russo, R.
Santen, and T. Sutter. 2006. Catechol estrogen quinones as initiators of breast and other human cancers:
implications for biomarkers of susceptibility and cancer prevention. Biochimica et Biophysica Acta 1766
(1):63–78.
Cavalieri, E. L., D. E. Stack, P. D. Devanesan, R. Todorovic, I. Dwivedy, S. Higginbotham, S. L. Johansson,
K. D. Patil, M. L. Gross, J. K. Gooden, R. Ramanathan, R. L. Cerny, and E. G. Rogan. 1997. Molecular
origin of cancer: catechol estrogen-3,4-quinones as endogenous tumor initiators. Proceedings of the
National Academy of Sciences of the United States of America 94 (20):10937–10942.
Chen, C.-Y., J.-H. Jang, M.-H. Li, and Y.-J. Surh. 2005. Resveratrol upregulates heme oxygenase-1 expres-
sion via activation of NF-E2-related factor 2 in PC12 cells. Biochemical and Biophysical Research
Communications 331 (4):993–1000.
Chen, Y. R., and T. H. Tan. 1998. Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by cur-
cumin. Oncogene 17 (2):173–178.
Cheung, K. L., T. O. Khor, M. T. Huang, and A. N. Kong. 2010. Differential in vivo mechanism of che-
moprevention of tumor formation in azoxymethane/dextran sodium sulfate mice by PEITC and DBM.
Carcinogenesis 31 (5):880–885.
Cheung, K. L., T. O. Khor, and A. N. Kong. 2009. Synergistic effect of combination of phenethyl isothiocya-
nate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation. Pharmaceutical
Research 26 (1):224–231.
Choi, K. C., M. G. Jung, Y. H. Lee, J. C. Yoon, S. H. Kwon, H. B. Kang, M. J. Kim, J. H. Cha, Y. J. Kim, W. J.
Jun, J. M. Lee, and H. G. Yoon. 2009. Epigallocatechin-3-gallate, a histone acetyltransferase inhibi-
tor, inhibits EBV-induced B lymphocyte transformation via suppression of RelA acetylation. Cancer
Research 69 (2):583–592.
Coussens, L. M., and Z. Werb. 2002. Inflammation and cancer. Nature 420 (6917):860–867.
Csiszar, A., K. Smith, N. Labinskyy, Z. Orosz, A. Rivera, and Z. Ungvari. 2006. Resveratrol attenuates TNF-
alpha-induced activation of coronary arterial endothelial cells: role of NF-kB inhibition. American
Journal of Physiology-Heart and Circulatory Physiology 291 (4):H1694–H1699.
Danielson, P. B. 2002. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in
humans. Current Drug Metabolism 3 (6):561–597.
Dashwood, R. H. 2002. Modulation of heterocyclic amine-induced mutagenicity and carcinogenicity: an ‘A-to-Z’
guide to chemopreventive agents, promoters, and transgenic models. Mutation Research 511 (2):89–112.
Dhillon, N., B. B. Aggarwal, R. A. Newman, R. A. Wolf, A. B. Kunnumakkara, J. L. Abbruzzese, C. S. Ng, V.
Badmaev, and R. Kurzrock. 2008. Phase II trial of curcumin in patients with advanced pancreatic cancer.
Clinical Cancer Research 14 (14):4491–4499.
Dinkova-Kostova, A. T., S. N. Jenkins, J. W. Fahey, L. Ye, S. L. Wehage, K. T. Liby, K. K. Stephenson, K. L.
Wade, and P. Talalay. 2006. Protection against UV-light-induced skin carcinogenesis in SKH-1 high-risk
mice by sulforaphane-containing broccoli sprout extracts. Cancer Letters 240 (2):243–252.
Doll, R., and R. Peto. 1981. The causes of cancer: quantitative estimates of avoidable risks of cancer in the
United States today. Journal of the National Cancer Institute 66 (6):1191–1308.
Emerit, J., M. Edeas, and F. Bricaire. 2004. Neurodegenerative diseases and oxidative stress. Biomedicine and
Pharmacotherapy 58 (1):39–46.
Fan, S., Q. Meng, T. Saha, F. H. Sarkar, and E. M. Rosen. 2009. Low concentrations of diindolylmethane, a
metabolite of indole-3-carbinol, protect against oxidative stress in a BRCA1-dependent manner. Cancer
Research 69 (15):6083–6091.
Feng, D., W.-H. Ling, and R.-D. Duan. 2010. Lycopene suppresses LPS-induced NO and IL-6 production by
inhibiting the activation of ERK, p38MAPK, and NF-κB in macrophages. Inflammation Research 59 (2):
115–121.
Feng, R., Y. Lu, L. L. Bowman, Y. Qian, V. Castranova, and M. Ding. 2005. Inhibition of activator protein-1,
NF-κB, and MAPKs and induction of phase 2 detoxifying enzyme activity by chlorogenic acid. Journal
of Biological Chemistry 280 (30):27888–27895.
Fisher, B., J. P. Costantino, D. L. Wickerham, C. K. Redmond, M. Kavanah, W. M. Cronin, V. Vogel, A.
Robidoux, N. Dimitrov, J. Atkins, M. Daly, S. Wieand, E. Tan-Chiu, L. Ford, and N. Wolmark. 1998.
Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel
Project P-1 Study. Journal of the National Cancer Institute 90 (18):1371–1388.
Garg, R., S. Gupta, and G. B. Maru. 2008. Dietary curcumin modulates transcriptional regulators of phase I and
phase II enzymes in benzo a pyrene-treated mice: mechanism of its anti-initiating action. Carcinogenesis
29 (5):1022–1032.
Giovannucci, E. 1999. Tomatoes, tomato-based products, lycopene, and cancer: review of the epidemiologic
literature. Journal of the National Cancer Institute 91 (4):317–331.
Gomaa, E. A., J. I. Gray, S. Rabie, C. Lopez-Bote, and A. M. Booren. 1993. Polycyclic aromatic hydrocarbons
in smoked food products and commercial liquid smoke flavourings. Food Additives and Contaminants
10 (5):503–521.
Gonzalez, F. J., and H. V. Gelboin. 1994. Role of human cytochromes P450 in the metabolic activation of
chemical carcinogens and toxins. Drug Metabolism Reviews 26 (1–2):165–183.
Guengerich, F. P. 1992. Metabolic activation of carcinogens. Pharmacology and Therapeutics 54 (1):17–61.
Hanahan, D., and R. A. Weinberg. 2000. The hallmarks of cancer. Cell 100 (1):57–70.
Henderson, B. E., and H. S. Feigelson. 2000. Hormonal carcinogenesis. Carcinogenesis 21 (3):427–433.
Henderson, B. E., R. K. Ross, and M. C. Pike. 1991. Toward the primary prevention of cancer. Science 254
(5035):1131–1118.
Henderson, B. E., R. K. Ross, M. C. Pike, and J. T. Casagrande. 1982. Endogenous hormones as a major factor
in human cancer. Cancer Research 42 (8):3232–3239.
Hoelzl, C., H. Glatt, W. Meinl, G. Sontag, G. Haidinger, M. Kundi, T. Simic, A. Chakraborty, J. Bichler, F. Ferk,
K. Angelis, A. Nersesyan, and S. Knasmuller. 2008. Consumption of Brussels sprouts protects peripheral
human lymphocytes against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and oxidative
DNA-damage: results of a controlled human intervention trial. Mol Nutr Food Res 52 (3):330–341.
Hong, F., M. L. Freeman, and D. C. Liebler. 2005. Identification of sensor cysteines in human Keap1 modified
by the cancer chemopreventive agent sulforaphane. Chemical Research in Toxicology 18 (12):1917–1926.
Hsieh, T. C., X. Lu, Z. Wang, and J. M. Wu. 2006. Induction of quinone reductase NQO1 by resveratrol in
human K562 cells involves the antioxidant response element ARE and is accompanied by nuclear trans-
location of transcription factor Nrf2. Medicinal Chemistry 2 (3):275–285.
Hu, R., C. J. Xu, G. X. Shen, M. R. Jain, T. O. Khor, A. Gopalkrishnan, W. Lin, B. Reddy, J. Y. Chan, and
A. N. T. Kong. 2006. Gene expression profiles induced by cancer chemopreventive isothiocyanate sul-
foraphane in the liver of C57BL/6J mice and C57BL/6J/Nrf2 (–/–) mice. Cancer Letters 243 (2):170–192.
Hussain, S. P., and C. C. Harris. 2007. Inflammation and cancer: an ancient link with novel potentials.
International Journal of Cancer 121 (11):2373–2380.
Hussain, S. P., L. J. Hofseth, and C. C. Harris. 2003. Radical causes of cancer. Nature Reviews Cancer
3 (4):276–285.
Itoh, K., T. Chiba, S. Takahashi, T. Ishii, K. Igarashi, Y. Katoh, T. Oyake, N. Hayashi, K. Satoh, I. Hatayama,
M. Yamamoto, and Y. Nabeshima. 1997. An Nrf2/small Maf heterodimer mediates the induction of
phase II detoxifying enzyme genes through antioxidant response elements. Biochemical and Biophysical
Research Communications 236 (2):313–322.
Jagerstad, M., K. Skog, S. Grivas, and K. Olsson. 1991. Formation of heterocyclic amines using model systems.
Mutation Research 259 (3–4):219–233.
Jang, J. H., and Y. J. Surh. 2001. Protective effects of resveratrol on hydrogen peroxide-induced apoptosis
in rat pheochromocytoma (PC12) cells. Mutation Research—Genetic Toxicology and Environmental
Mutagenesis 496 (1–2):181–190.
Jemal, A., R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun. 2009. Cancer Statistics, 2009. CA: A Cancer
Journal for Clinicians 59 (4):225–249.
Jeong, W. S., M. Jun, and A. N. Kong. 2006. Nrf2: a potential molecular target for cancer chemoprevention by
natural compounds. Antioxidants and Redox Signaling 8 (1–2):99–106.
Jernstrom, B., M. Funk, H. Frank, B. Mannervik, and A. Seidel. 1996. Glutathione S-transferase A1-1-catalysed
conjugation of bay and fjord region diol epoxides or polycyclic aromatic hydrocarbons with glutathione.
Carcinogenesis 17 (7):1491–1498.
Khor, T. O., Y. S. Keum, W. Lin, J. H. Kim, R. Hu, G. Shen, C. Xu, A. Gopalakrishnan, B. Reddy, X. Zheng, A. H.
Conney, and A. N. Kong. 2006. Combined inhibitory effects of curcumin and phenethyl isothiocyanate on
the growth of human PC-3 prostate xenografts in immunodeficient mice. Cancer Research 66 (2):613–621.
Knasmuller, S., D. M. DeMarini, I. Johnson, and C. Gerhauser, eds. 2009. Chemoprevention of Cancer and
DNA Damage by Dietary Factors. Wiley-Blackwell.
Knize, M. G., K. S. Kulp, C. P. Salmon, G. A. Keating, and J. S. Felton. 2002. Factors affecting human hetero-
cyclic amine intake and the metabolism of PhIP. Mutation Research 506–507:153–162.
Lee, M., D.-W. Han, S.-H. Hyon, and J.-C. Park. 2011. Apoptosis of human fibrosarcoma HT-1080 cells by
epigallocatechin-3-O-gallate via induction of p53 and caspases as well as suppression of Bcl-2 and phos-
phorylated nuclear factor-κB. Apoptosis 16 (1):75–85.
Li, L. C., P. R. Carroll, and R. Dahiya. 2005. Epigenetic changes in prostate cancer: Implication for diagnosis
and treatment. Journal of the National Cancer Institute 97 (2):103–115.
Lian, F., and X. D. Wang. 2008. Enzymatic metabolites of lycopene induce Nrf2-mediated expression of phase
II detoxifying/antioxidant enzymes in human bronchial epithelial cells. International Journal of Cancer
123 (6):1262–1268.
Lin, W., R. T. Wu, T. Wu, T.-O. Khor, H. Wang, and A.-N. Kong. 2008. Sulforaphane suppressed LPS-
induced inflammation in mouse peritoneal macrophages through Nrf2 dependent pathway. Biochemical
Pharmacology 76 (8):967–973.
Lu, H., W. Ouyang, and C. Huang. 2006. Inflammation, a key event in cancer development. Molecular Cancer
Research 4 (4):221–233.
Maheo, K., F. Morel, S. Langouet, H. Kramer, E. Le Ferrec, B. Ketterer, and A. Guillouzo. 1997. Inhibition of
cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and
rat hepatocytes. Cancer Research 57 (17):3649–3652.
Majid, S., A. A. Dar, A. E. Ahmad, H. Hirata, K. Kawakami, V. Shahryari, S. Saini, Y. Tanaka, A. V. Dahiya, G.
Khatri, and R. Dahiya. 2009. BTG3 tumor suppressor gene promoter demethylation, histone modifica-
tion and cell cycle arrest by genistein in renal cancer. Carcinogenesis 30 (4):662–670.
Majid, S., N. Kikuno, J. Nelles, E. Noonan, Y. Tanaka, K. Kawamoto, H. Hirata, L. C. Li, H. Zhao, S. T. Okino,
R. F. Place, D. Pookot, and R. Dahiya. 2008. Genistein induces the p21WAF1/CIP1 and p16INK4a tumor
suppressor genes in prostate cancer cells by epigenetic mechanisms involving active chromatin modifica-
tion. Cancer Research 68 (8):2736–2744.
Meador, J. P., J. E. Stein, W. L. Reichert, and U. Varanasi. 1995. Bioaccumulation of polycyclic aromatic hydro-
carbons by marine organisms. Reviews of Environmental Contamination and Toxicology 143:79–165.
Moolgavkar, S. H. 1978. The multistage theory of carcinogenesis and the age distribution of cancer in man.
Journal of the National Cancer Institute 61 (1):49–52.
Na, H.-K., E.-H. Kim, J.-H. Jung, H.-H. Lee, J.-W. Hyun, and Y.-J. Surh. 2008. (-)-Epigallocatechin gallate
induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mam-
mary epithelial cells. Archives of Biochemistry and Biophysics 476 (2):171–177.
Nair, S., A. Barve, T.-O. Khor, G.-X. Shen, W. Lin, J. Y. Chan, L. Cai, and A.-N. Kong. 2010. Regulation of
Nrf2- and AP-1-mediated gene expression by epigallocatechin-3-gallate and sulforaphane in prostate of
Nrf2-knockout or C57BL/6J mice and PC-3 AP-1 human prostate cancer cells. Acta Pharmacologica
Sinica 31 (9):1223–1240.
Nakai, Y., W. G. Nelson, and A. M. De Marzo. 2007. The dietary charred meat carcinogen 2-amino-1-methyl-
6-phenylimidazo[4,5-b]pyridine acts as both a tumor initiator and promoter in the rat ventral prostate.
Cancer Research 67 (3):1378–1384.
Nardini, M., F. Leonardi, C. Scaccini, and F. Virgili. 2001. Modulation of ceramide-induced NF-kappa B bind-
ing activity and apoptotic response by caffeic acid in U937 cells: Comparison with other antioxidants.
Free Radical Biology and Medicine 30 (7):722–733.
Nishinaka, T., Y. Ichijo, M. Ito, M. Kimura, M. Katsuyama, K. Iwata, T. Miura, T. Terada, and C. Yabe-
Nishimura. 2007. Curcumin activates human glutathione S-transferase P1 expression through antioxidant
response element. Toxicology Letters 170 (3):238–247.
Nouso, K., S. S. Thorgeirsson, and N. Battula. 1992. Stable expression of human cytochrome P450IIE1 in
mammalian cells: metabolic activation of nitrosodimethylamine and formation of adducts with cellular
DNA. Cancer Research 52 (7):1796–1800.
Parkin, D. M. 2001. Global cancer statistics in the year 2000. Lancet Oncology 2 (9):533–543.
Paul, G., F. Bataille, F. Obermeier, J. Bock, F. Klebl, U. Strauch, D. Lochbaum, P. Rummele, S. Farkas, J.
Scholmerich, M. Fleck, G. Rogler, and H. Herfarth. 2005. Analysis of intestinal haem-oxygenase-1
(HO-1) in clinical and experimental colitis. Clinical and Experimental Immunology 140 (3):547–555.
Phillips, D. H. 1999. Polycyclic aromatic hydrocarbons in the diet. Mutation Research 443 (1–2):139–147.
Phillips, D. H. 1983. Fifty years of benzo(a)pyrene. Nature 303 (5917):468–472.
Pool-Zobel, B., S. Veeriah, and F. D. Bohmer. 2005. Modulation of xenobiotic metabolising enzymes by anti-
carcinogens—focus on glutathione S-transferases and their role as targets of dietary chemoprevention in
colorectal carcinogenesis. Mutation Research 591 (1–2):74–92.
Poyton, R. O., K. A. Ball, and P. R. Castello. 2009. Mitochondrial generation of free radicals and hypoxic sig-
naling. Trends in Endocrinology and Metabolism 20 (7):332–340.
Ramos-Gomez, M., M. K. Kwak, P. M. Dolan, K. Itoh, M. Yamamoto, P. Talalay, and T. W. Kensler. 2001.
Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2
transcription factor-deficient mice. Proceedings of the National Academy of Sciences of the United States
of America 98 (6):3410–3415.
Reuter, S., S. C. Gupta, M. M. Chaturvedi, and B. B. Aggarwal. 2010. Oxidative stress, inflammation, and
cancer How are they linked? Free Radical Biology and Medicine 49 (11):1603–1616.
Rice, S., and S. A. Whitehead. 2006. Phytoestrogens and breast cancer—promoters or protectors? Endocrine-
Related Cancer 13 (4):995–1015.
Ross, R. K., M. C. Pike, G. A. Coetzee, J. K. Reichardt, M. C. Yu, H. Feigelson, F. Z. Stanczyk, L. N. Kolonel,
and B. E. Henderson. 1998. Androgen metabolism and prostate cancer: establishing a model of genetic
susceptibility. Cancer Research 58 (20):4497–4504.
Rustemeier, K., R. Stabbert, H. J. Haussmann, E. Roemer, and E. L. Carmines. 2002. Evaluation of the poten-
tial effects of ingredients added to cigarettes. Part 2: Chemical composition of mainstream smoke. Food
and Chemical Toxicology 40 (1):93–104.
Sharma, C., J. Kaur, S. Shishodia, B. B. Aggarwal, and R. Ralhan. 2006. Curcumin down regulates smokeless
tobacco-induced NF-kappa B activation and COX-2 expression in human oral premalignant and cancer
cells. Toxicology 228 (1):1–15.
Shimada, T., C. L. Hayes, H. Yamazaki, S. Amin, S. S. Hecht, F. P. Guengerich, and T. R. Sutter. 1996.
Activation of chemically diverse procarcinogens by human cytochrome P-450 1B1. Cancer Research
56 (13):2979–2984.
Shu, L., K.-L. Cheung, T. Khor, C. Chen, and A.-N. Kong. 2010. Phytochemicals: cancer chemoprevention and
suppression of tumor onset and metastasis. Cancer and Metastasis Reviews 29 (3):483–502.
Singh, R., S. Ahmed, N. Islam, V. M. Goldberg, and T. M. Haqqi. 2002. Epigallocatechin-3-gallate inhibits
interleukin-1 beta-induced expression of nitric oxide synthase and production of nitric oxide in human
chondrocytes—suppression of nuclear factor kappa B activation by degradation of the inhibitor of nuclear
factor kappa B. Arthritis and Rheumatism 46 (8):2079–2086.
Skog, K. I., M. A. Johansson, and M. I. Jagerstad. 1998. Carcinogenic heterocyclic amines in model sys-
tems and cooked foods: a review on formation, occurrence and intake. Food and Chemical Toxicology
36 (9–10):879–896.
Sugimura, T., K. Wakabayashi, H. Nakagama, and M. Nagao. 2004. Heterocyclic amines: Mutagens/carcino-
gens produced during cooking of meat and fish. Cancer Science 95 (4):290–299.
Surh, Y. J., K. S. Chun, H. H. Cha, S. S. Han, Y. S. Keum, K. K. Park, and S. S. Lee. 2001. Molecular mecha-
nisms underlying chemopreventive activities of anti-inflammatory phytochemicals: Down-regulation of
COX-2 and iNOS through suppression of NF-kappa B activation. Mutation Research—Fundamental and
Molecular Mechanisms of Mutagenesis 480:243–268.
Surh, Y.-J. 2003. Cancer chemoprevention with dietary phytochemicals. Nature Reviews Cancer 3 (10):768–780.
Talalay, P. 2000. Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors 12 (1–4):5–11.
Tang, L. L., T. Y. Jin, X. B. Zeng, and J. S. Wang. 2005. Lycopene inhibits the growth of human androgen-
independent prostate cancer cells in vitro and in BALB/c nude mice. Journal of Nutrition 135
(2):287–290.
Thomasset, S. C., D. P. Berry, G. Garcea, T. Marczylo, W. P. Steward, and A. J. Gescher. 2007. Dietary polyphe-
nolic phytochemicals—promising cancer chemopreventive agents in humans? A review of their clinical
properties. International Journal of Cancer 120 (3):451–458.
Tricker, A. R., and R. Preussmann. 1991. Carcinogenic N-nitrosamines in the diet: occurrence, formation,
mechanisms and carcinogenic potential. Mutation Research 259 (3–4):277–289.
Valko, M., D. Leibfritz, J. Moncol, M. T. D. Cronin, M. Mazur, and J. Telser. 2007. Free radicals and antioxi-
dants in normal physiological functions and human disease. International Journal of Biochemistry &
Cell Biology 39 (1):44–84.
Wakabayashi, N., K. Itoh, J. Wakabayashi, H. Motohashi, S. Noda, S. Takahashi, S. Imakado, T. Kotsuji, F.
Otsuka, D. R. Roop, T. Harada, J. D. Engel, and M. Yamamoto. 2003. Keap1-null mutation leads to post-
natal lethality due to constitutive Nrf2 activation. Nature Genetics 35 (3):238–245.
Wattenberg, L. W. 1992. Inhibition of carcinogenesis by minor dietary constituents. Cancer Research 52 (7
Suppl):2085s–2091s.
Wattenberg, L. W. 1985. Chemoprevention of Cancer. Cancer Research 45 (1):1–8.
Wattenberg, L. W. 1977. Inhibition of carcinogenic effects of polycyclic hydrocarbons by benzyl isothiocyanate
and related compounds. Journal of the National Cancer Institute 58 (2):395–398.
Wattenberg, L. W. 1966. Chemoprophylaxis of carcinogenesis: a review. Cancer Research 26 (7):1520–1526.
WHO, World Health Organization. 2011. The 10 Leading Causes of Death by Broad Income Group (2008).
http://www.who.int/mediacentre/factsheets/fs310/en/
Wiegand, H., A. E. Wagner, C. Boesch-Saadatmandi, H. P. Kruse, S. Kulling, and G. Rimbach. 2009. Effect
of dietary genistein on Phase II and antioxidant enzymes in rat liver. Cancer Genomics Proteomics
6 (2):85–92.
Williams, G. M. 1977. Detection of chemical carcinogens by unscheduled DNA synthesis in rat liver primary
cell cultures. Cancer Research 37 (6):1845–1851.
Wogan, G. N., S. S. Hecht, J. S. Felton, A. H. Conney, and L. A. Loeb. 2004. Environmental and chemical
carcinogenesis. Seminars in Cancer Biology 14 (6):473–486.
Wu, Y. N., H. Z. Wang, J. S. Li, and C. Han. 1993. The inhibitory effect of Chinese tea and its polyphenols on
in vitro and in vivo N-nitrosation. Biomedical and Environmental Sciences 6 (3):237–258.
Xu, C., G. Shen, C. Chen, C. Gelinas, and A. N. Kong. 2005. Suppression of NF-kappaB and NF-kappaB-
regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human
prostate cancer PC-3 cells. Oncogene 24 (28):4486–4495.
Xu, C., X. Yuan, Z. Pan, G. Shen, J. H. Kim, S. Yu, T. O. Khor, W. Li, J. Ma, and A. N. Kong. 2006. Mechanism
of action of isothiocyanates: The induction of ARE-regulated genes is associated with activation of ERK
and JNK and the phosphorylation and nuclear translocation of Nrf2. Molecular Cancer Therapeutics
5 (8):1918–1926.
Xu, J., K. D. Kochanek, S. L. Murphy, B. Tejada-Vera. 2010. Deaths: Final Data for 2007. National Vital
Statistics Reports, vol 58 no 19. Hyattsville, MD: National Center for Health Statistics.
Yager, J. D., and N. E. Davidson. 2006. Estrogen carcinogenesis in breast cancer. New England Journal of
Medicine 354 (3):270–282.
Yang, Chung S., Jeong-Sook H. Yoo, Hiroyuki Ishizaki, and Junyan Hong. 1990. Cytochrome P450IIe1: Roles
in nitrosamine metabolism and mechanisms of regulation. Drug Metabolism Reviews 22 (2–3):147–159.
Zhang, Y., and P. Talalay. 1994. Anticarcinogenic activities of organic isothiocyanates: chemistry and mecha-
nisms. Cancer Research 54 (7 Suppl):1976s–1981s.
Zhao, Y., Y. Xue, T. D. Oberley, K. K. Kiningham, S. M. Lin, H. C. Yen, H. Majima, J. Hines, and D. St
Clair. 2001. Overexpression of manganese superoxide dismutase suppresses tumor formation by mod-
ulation of activator protein-1 signaling in a multistage skin carcinogenesis model. Cancer Research
61 (16):6082–6088.
Zhu, B. T., D. P. Loder, M. X. Cai, C. T. Ho, M. T. Huang, and A. H. Conney. 1998. Dietary administration of
an extract from rosemary leaves enhances the liver microsomal metabolism of endogenous estrogens and
decreases their uterotropic action in CD-1 mice. Carcinogenesis 19 (10):1821–1827.
2 Overview of Obesity,
Inflammation, and Cancer
Ximena Paredes-Gonzalez, Tin Oo Khor, Limin Shu,
Constance Lay-Lay Saw, and Ah-Ng Tony Kong
CONTENTS
2.1 Introduction............................................................................................................................. 21
2.2 Obesity and Cancer Risk......................................................................................................... 22
2.2.1 Breast Cancer............................................................................................................... 23
2.2.2 Endometrial and Colorectal Cancers...........................................................................24
2.2.3 Esophageal and Pancreatic Cancers............................................................................24
2.2.4 Kidney and Prostate Cancers.......................................................................................25
2.2.5 Others Types of Cancer...............................................................................................25
2.3 Molecular Pathways.................................................................................................................26
2.3.1 Insulin and IGF-1.........................................................................................................26
2.3.2 Chronic Inflammation................................................................................................. 27
2.3.3 Leptin, Adiponectin, and Estrogen.............................................................................. 27
2.3.4 Microenvironment Changes........................................................................................28
2.3.5 Changes in Lipid Availability...................................................................................... 29
2.3.6 Other Pathways............................................................................................................ 29
2.4 Perspectives on Chemoprevention........................................................................................... 30
References......................................................................................................................................... 30
2.1 INTRODUCTION
Obesity has reached epidemic proportions and is recognized as a major cause of cancer worldwide
(World Health Organization 2000, 2011). Obesity can be defined as an excess of body adiposity,
which is evaluated according to the body weight. The body mass index (BMI) correlates weight and
height (BMI = weight in kilograms divided by the square of the height in meters [kg/m2]), and since
1980, BMI has been considered the standard measure for evaluating whether a person is obese. In
general, an individual with a BMI between 25 and 30 is classified as overweight or pre-obese, while
an individual with a BMI over 30 is classified as obese; different intervals are established according
to the mortality risk (Table 2.1) (Caballero 2007; World Health Organization 2000).
Although data from the United States indicate that the incidence of obesity is increasing slowly
or leveling off when compared to the past decade (Flegal et al. 2010, 2012), more than 1 billion
people worldwide are overweight or obese (Deitel 2003). It has been estimated that 14% and 20%
of all cancer deaths in men and women, respectively, can be attributed to excess body weight (Calle
et al. 2003, 2004; Wolin et al. 2010). Obesity is associated with some types of cancer (Simard et al.
2012), such as colon, breast (postmenopausal), endometrial, kidney (renal cell), esophageal (adeno-
carcinoma), pancreatic, colorectal, and, potentially, gall bladder carcinoma (Wiseman 2008; Vainio
et al. 2002). In addition, a prospective study published in 2003 that considered more than 900,000
21
TABLE 2.1
International Classification of Underweight, Overweight,
and Obese Adults According to BMI
Classification BMI
Underweight <18.50
Normal range 18.50–24.99
Overweight ≥25.00
Pre-obese 25.00–29.99
Obese ≥30.00
Class I 30.00–34.99
Class II 35.00–39.99
Class III ≥40.00
Sources: WHO, Physical status: the use and interpretation of anthropometry,

Report of a WHO Expert Committee. WHO Technical Report Series
854. Geneva: World Health Organization, 1995. http://whqlibdoc.
who.int/trs/WHO_TRS_854.pdf; World Health Organization. Obesity:
preventing and managing the global epidemic: report of a WHO con-
sultation, WHO technical report series, Geneva: World Health
Organization, 2000, http://whqlibdoc.who.int/trs/WHO_TRS_894.
pdf, WHO Expert Consultation, Appropriate body-mass index for
Asian populations and its implications for policy and intervention
strategies, The Lancet 157–163, 2004, http://www.ncbi.nlm.nih.gov/
pubmed/14726171?dopt=Abstract.
US adults found that non-Hodgkin’s lymphoma, prostate cancer, and multiple myeloma are also
associated with obesity (Calle et al. 2003).
If obesity can be controlled, the incidence and mortality of obesity-associated cancers may be
reduced significantly with weight loss (Sedjo et al. 2007). The American Cancer Society (ACS)
Board of Directors has proposed the ambitious and challenging goal of reducing cancer mortality by
50% and cancer incidence by 25% by the year 2015 (Byers et al. 1999; ACS 1996, 1998). Moreover, a
better understanding of the relationship between cancer and obesity, beyond epidemiology and basic
research, may lead to the development of new targeted therapies to prevent obesity-related cancers.
2.2 OBESITY AND CANCER RISK

An association between obesity and cancer was clearly observed in an experimental setting as early
as the 1940–1950s, when overfed animals exhibited a higher incidence of neoplasia (Finkel et al.
1955). In 1949, Waxler and Brecher developed a novel obese murine model by injecting mice with a
single dose of gold thioglucose, and in 1953, Waxler reported that these obese mice developed spon-
taneous mammary tumors earlier than nonobese controls (Brecher et al. 1949; Waxler et al. 1953).
Lew and Garfinkel in 1979 published the first significant epidemiological evidence that excessive
weight or obesity increases the risk of mortality from cancer (Lew et al. 1979). Since then, experi-
mental and clinical studies have yielded a vast amount of information.
A meta-analysis of data from prospective studies published between 1966 and 1997 for six cancer
types (breast, colon, endometrial, prostate, kidney, and gallbladder) reported that 3% and 6% of the
attributable risks for men and women, respectively, were caused by excessive body mass (Bergstrom
et al. 2001b). Other studies that included more types of cancers have confirmed these findings and
reported a higher population-attributable risk in women (Renehan et al. 2008, 2010). In addition, for
Overview of Obesity, Inflammation, and Cancer 23
all cancers combined, the male and female populations with the highest BMI values (class III) have
death rates that are 52% and 62% higher, respectively, than those of populations with normal weight
(Calle et al. 2003). Therefore, it is now well established that being overweight or obese increases
the risk of developing and dying from cancer (Calle et al. 1999, 2003; Berrington de Gonzalez et al.
2010; Lee et al. 2010; Parr et al. 2010; Samanic et al. 2004). A 5 kg/m² increase in BMI is signifi-
cantly associated with esophageal adenocarcinoma in both sexes; thyroid, colon, and renal cancers
in men; and endometrial, gallbladder, and renal cancers in women (Renehan et al. 2008).
Furthermore, it is not surprising that losing weight can reduce the probability of developing can-
cer; thus, gastric bypass has been found to decrease cancer risk by 24% and the risk of death from
cancer by 46% (Adams et al. 2009). Interestingly, this impact is especially significant in women,
for whom surgery decreases the overall risk of cancer by 42% (Sjostrom et al. 2009), with a large
impact on breast and endometrial cancers (Ashrafian et al. 2011). As mentioned previously, weight
gain has a larger effect on female cancer development than male cancer development; moreover,
the Million Women Study developed in the United Kingdom, which included a 5.4-year follow-up
for cancer incidence and a 7-year follow-up for cancer mortality, revealed a significant increase in
cancer incidence and mortality risks with increasing BMI for 10 of 17 cancers that were examined
in women 50 years of age or older (Reeves et al. 2007).
2.2.1 Breast Cancer
Although breast cancer incidence rates in the United States were stable in 2004–2008 (DeSantis et
al. 2011), breast cancer still represents the most common cause of death among Hispanic women and
the second most common cause of death among white, black, Asian/Pacific Islander, and American
Indian/Alaska Native women (US Cancer Statistics 2010), with different epidemiological traits in
premenopausal and postmenopausal women (Smigal et al. 2006; DeSantis et al. 2011). Obese women
have an increased risk of cancer (Parker et al. 2003; Singh et al. 2011; Chlebowski 2012) and a poorer
survival prognosis than lean women (Protani et al. 2010; Ewertz et al. 2011; Goodwin et al. 2002,
2012). Obesity has been associated with an increased risk of postmenopausal breast cancer (Renehan
et al. 2008; Key et al. 2003; La Vecchia et al. 2011), but the effect of obesity on premenopausal
women is controversial because some studies have demonstrated a negative relationship (Renehan et
al. 2008; Fagherazzi et al. 2012; Michels et al. 2012; Vrieling et al. 2010; Baer et al. 2010).
Women older than 50 years of age, who are usually postmenopausal, constitute the majority of
breast cancer diagnoses; until recently, the incidence of breast cancer has followed an increasing trend
in this group. Among postmenopausal women, nulliparity and obesity are associated with a higher
risk of breast cancer incidence and mortality, particularly in non–hormone therapy users (Ogden et
al. 2006). Obesity has been associated with the production of increased levels of estrogen in adipose
tissue (Cleary et al. 2009), which is positively correlated with tumors that express estrogen hormone
receptors (ERs) and progesterone (PG) hormone receptors (Yang et al. 2011; Esfahlan et al. 2011).
In premenopausal women, who constitute approximately 35% of breast cancer diagnoses
(Howlader 2011), the risk of breast cancer is more likely to be associated with genetic predisposition
(Singletary 2003), and the effects of obesity are unclear. Nevertheless, epidemiological data from the
Iowa Women’s Health Study have suggested that weight gain between 18 years of age and menopause
is consistently associated with a higher risk of developing breast cancer after menopause (Harvie et
al. 2005), particularly hormone receptor–sensitive breast cancer (Suzuki et al. 2011). In addition,
breast cancer survival may be reduced in premenopausal women (Abrahamson et al. 2006).
The relationship between obesity and breast cancer risk varies among different races and ethnici-
ties. Some studies have shown that obesity plays an important role in breast cancer in Caucasian
women but may not have an influence in Hispanic women (Sarkissyan et al. 2011; Abdel-Maksoud
et al. 2012). In Hispanic women, breast cancer is increasingly diagnosed at a younger age, with
a more advanced stage at diagnosis and worse prognosis than for non-Hispanic whites. In addi-
tion, this group is more likely to have estrogen receptor–negative tumors (Abdel-Maksoud et al.
2012). However, it remains unclear whether obesity plays a role in this trend. In African-American
women, the link between obesity and cancer risk is controversial; despite higher rates of obesity,
BMI differences do not explain the reduced breast cancer survival in this group (Eley et al. 1994;
McCullough et al. 2005; Chlebowski et al. 2005). A recent case–control study found an important
role for obesity in influencing adverse outcomes (development of distant metastases and death from
breast cancer) in white but not black women with breast cancer (Lu et al. 2011). In Asian women, a
stronger association between obesity and breast cancer has been observed for both postmenopausal
and premenopausal women (Renehan et al. 2008; Parr et al. 2010).
2.2.2 Endometrial and Colorectal Cancers

Excess weight and obesity increase the risk of endometrial cancer by more than 40% (Renehan et
al. 2008, 2010; Olsen et al. 2007) and are associated with a poor prognosis (Calle et al. 2003; von
Gruenigen et al. 2006). There appears to be a linear weight–risk relationship between increased
BMI and endometrial cancer risk (Schouten et al. 2004). This association appears to be indepen-
dent of menopausal status but has a stronger effect in postmenopausal woman, particularly those
who have never used hormone replacement therapy (Soliman et al. 2005; Friedenreich et al. 2007).
Through the aromatization of estrogen precursors (Cauley et al. 1989) as well as inflammation
and insulin resistance (Wang et al. 2011), excessive estrogen production by adipose tissue in obese
women has been suggested to play a complex role in the relationship between obesity and endo-
metrial cancer. Furthermore, obesity in combination with diabetes (Parazzini et al. 1999; Shoff et
al. 1998; Anderson et al. 2001; Friberg, Orsini et al. 2007; Lindemann et al. 2008) and a lack of
exercise (Friberg et al. 2006; Patel et al. 2008) has been associated with a poor predictive outcome
(Lucenteforte et al. 2007; Friberg et al. 2007; Chia et al. 2007).
Obesity is associated with an increased risk of colorectal cancer in both men and women
(Giovannucci et al. 1995; Larsson et al. 2006; Larsson and Wolk 2007b; Dai et al. 2007; Yamamoto
et al. 2010; Hong et al. 2012), with a stronger association in men. Interestingly, compared to cancer
in the proximal or distal colon, the distribution of fat may play a greater role in the increased risk
of colorectal cancer, particularly in men, who more often develop abdominal obesity (Moore et al.
2004; Dai et al. 2007; Kim et al. 2009). The endocrine and paracrine effects of adipose tissue may
lead to systemic alterations such as chronic inflammation and alterations in the levels of adipokines,
sex steroids, insulin, insulin-related growth factor (including proinsulin and insulin-like growth fac-
tors [IGFs] 1 and 2), and vascular endothelial growth factor (VEGF), which may play an important
effect in promoting colon cancer development (Donohoe et al. 2011; Lysaght et al. 2011).
2.2.3 Esophageal and Pancreatic Cancers

Like colorectal cancer, esophageal adenocarcinoma has been strongly associated with obesity (par-
ticularly abdominal obesity), through similar mechanisms; the incidence of esophageal adenocarci-
noma is four times higher in obese patients (Lagergren et al. 1999; MacInnis et al. 2006; Renehan
et al. 2008; Ogunwobi et al. 2008; Lysaght et al. 2011; Doyle et al. 2012; Donohoe et al. 2012), and
men exhibit the strongest association between obesity and esophageal adenocarcinoma (Ryan et al.
2006; Kubo et al. 2006). Obesity may exacerbate esophageal inflammation, particularly in the pres-
ence of esophageal reflux (Hampel et al. 2005; Corley et al. 2006); however, the effect of obesity on
Barrett’s esophagus remains unclear (Corley et al. 2007; Cook et al. 2008; Seidel et al. 2009), as does
the association between obesity and squamous carcinoma (Steffen et al. 2009; Samanic et al. 2006).
There is a slightly increased risk of pancreatic cancer in both men and women who are overweight
or obese (Berrington de Gonzalez et al. 2003; Larsson et al. 2007; Jiao et al. 2010), particularly for
individuals with abdominal obesity (Larsson et al. 2005; Luo et al. 2008). It has been suggested
that obesity is correlated with an earlier age of disease in a dose–response manner (Genkinger et al.
2011), with lower overall survival in older patients (Li et al. 2009).
2.2.4 Kidney and Prostate Cancers

In 2008, Renehan et al. reported a strong association between obesity and renal cancer in both men
and women, which has been confirmed by several studies (Lindblad et al. 1994; Chow et al. 2000;
van Dijk et al. 2004; Bjorge et al. 2004; Flaherty et al. 2005; Lukanova et al. 2006; Pischon et al.
2006; Luo et al. 2007; Dal Maso et al. 2007; Adams et al. 2008; Ildaphonse et al. 2009; Mathew
et al. 2009; Renehan et al. 2010). In renal cell carcinoma, which represents the majority of kidney
cancers, this relationship appears to be stronger in obese women (Chow et al. 1996; Shapiro et al.
1999; Bergstrom et al. 2001a; Chiu et al. 2006). The mechanisms by which obesity may increase
renal cell cancer risk and progression are poorly understood (Klinghoffer et al. 2009; Chow et al.
2010), but hormonal changes, such as increased levels of leptin and decreased levels of adiponectin,
hyperinsulinemia and increases in related insulin growth factors, and increased levels of estrogen,
lipid peroxidation, and defects in the immune response, may be responsible (Jiao et al. 2010; Moyad
2001; Pischon et al. 2006; Gago-Dominguez et al. 2006; Horiguchi et al. 2006; Spyridopoulos et al.
2007, 2009). Interestingly, in patients with renal cell carcinoma and melanoma, a mutation in small
ubiquitin-like modifier (SUMO) on microphthalmia-associated transcription factor was identified,
which could impair the adaptation of cells to stress and initiate tumor formation, thus increasing
the risk of developing renal cell carcinoma, melanoma, or both fivefold (Bertolotto et al. 2011).
However, the mechanism (if any) by which this genetic predisposition may be correlated with obe-
sity remains to be elucidated.
The relationship between obesity and prostate cancer has been extensively studied but is not
completely conclusive (De Nunzio et al. 2012). Obesity may cause stromal changes in sex steroid
production and signaling pathways, which may affect prostate cancer growth via intracrine/para-
crine mechanisms involving certain hormones and growth factors such as IGF-1 (Gross et al. 2009;
Fowke et al. 2012). Three large, prospective cohort studies performed in the United States found
that obesity is not associated with prostate cancer and may even reduce the risk of less aggressive
tumors while increasing the risk of more aggressive tumors (Rodriguez et al. 2001, 2007; Gong et al.
2006), with a positive mortality association (Bassett et al. 2011; Cao et al. 2011; Parr et al. 2010). A
recent meta-analysis suggests that obesity may have the dual effect of decreasing the risk for local-
ized prostate cancer and increasing the risk for advanced prostate cancer (Discacciati et al. 2012).
This apparent paradox may be explained by the reduced detectability of prostate cancer among
obese men with asymptomatic, clinically localized disease (Freedland et al. 2008). Parekh et al.
(2010) analyzed three representative cross-sectional surveys in the United States (National Health and
Nutrition Examination Survey [NHANES] III, NHANES 2001–2004, and National Health Interview
Survey [NHIS] 2000) and concluded that the prostate-specific antigen (PSA)–driven biopsy rates are
lower in men with BMIs above 30. In fact, overweight men may have more frequent PSA screening
(Fontaine et al. 2005), but due to a possible hemodilution from their large plasma volume (Lopez
Fontana et al. 2011), their PSA levels may appear normal, leading to lower biopsy rates in this group.
Moreover, obesity is associated with a larger prostate size, which may also affect the early detection of
prostate cancer (Kopp et al. 2011). Therefore, to clarify the relationship between obesity and prostate
cancer, further studies considering all of these factors are needed.
2.2.5 Others Types of Cancer

Diverse meta-analyses reporting a positive correlation between excessive body weight and the risk
of cancer have been published for gallbladder cancer (Larsson and Wolk 2007d), non-Hodgkin’s
lymphoma, Hodgkin’s lymphoma (Larsson and Wolk 2007c; Larsson et al. 2011), leukemia (Larsson
et al. 2008b), liver cancer (Larsson and Wolk 2007e), and, possibly, myeloma (Larsson and Wolk
2007a; Wallin et al. 2011). In addition, obesity may be involved in the development of nonalcoholic,
fatty liver disease contributing to the development of hepatocellular carcinoma (Nair et al. 2002;
Caldwell et al. 2004; Larsson et al. 2008a). The mechanisms involved are not well understood but
may involve the same mechanisms previously discussed, such as increased levels of hormones,
inflammation, and immunity impairment.
2.3 MOLECULAR PATHWAYS
The mechanism(s) by which obesity contributes to some or all of the hallmarks of cancer is an open ques-
tion. Although the link between cancer and obesity has been clearly demonstrated by many epidemiological
studies and several molecular pathways have been proposed (Khandekar et al. 2011), the interaction between
obesity and cancer development and progression remains poorly understood. A cooperative mechanism
involving increased insulin and IGF-1 axis signaling, chronic inflammation, changes in adipokine levels,
increased availability of lipids and hormones, microenvironment changes, and immunity impairment, as
well as genetic factors, may play a role in the conversion of normal e pithelial cells to an invasive tumor.
2.3.1 Insulin and IGF-1

Weight gain induces progressive metabolic dysfunction, leading to insulin resistance, in which
metabolic tissues (adipose tissue, liver, and muscle) are unable to respond to the anabolic actions of
insulin. Thus, impaired glucose disposal in muscle and enhanced triglyceride lipolysis in adipose
tissue results in hyperinsulinemia, hyperglycemia, and hyperlipidemia. As a compensatory mecha-
nism, β-pancreatic cells subsequently increase the production of insulin, and the liver, which exhib-
its partial insulin resistance, performs lipogenesis but not gluconeogenesis. As a result, the β-cells
become exhausted and contribute to sustained hyperglycemia and type 2 diabetes.
High levels of insulin and IGF-1 may promote tumor growth in a cooperative manner through a
variety of pathways such as the phosphatidylinositol-3-kinase (PI3K) and serine/threonine protein
kinase Akt (or protein kinase B [PKB]), Mammalian target of rapamycin (mTOR), S6 kinase, and
mitogen-activated protein kinase pathways (Pollak et al. 2004). Insulin and insulin-related growth
factors exert their effects after interacting with the tyrosine kinase receptors on the cell surface,
which are homologous to the tyrosine kinase class oncogenes. The insulin receptor (INSR) exists
in two variant isoforms, A and B. INSR isoform A interacts with insulin and IGF, whereas isoform
B, which is more commonly expressed on tumors, interacts just with insulin. The IGF-1 receptor
(IGF-1R) is a hybrid receptor that is able to interact with insulin as well as IGF-1 (Pollak 2012).
The downstream signaling pathways of insulin and IGF-1 are similar but not identical; insulin
and IGF-1 can concurrently activate both the PI3K and mitogen-activated protein kinase (MAPK)
pathways. After binding to its receptor, insulin induces extracellular signal–regulated kinase (ERK)
activation through growth factor receptor bound 2/SHC-son of Sevenless (GRB2/SHC-SOS)–Ras–
Raf and may also activate p38 and Jun kinase (JNK) with a regulatory role exerted by p85 (PI3K
regulatory subunit), inducing cell cycle arrest and apoptosis (Moxham et al. 1996; Antonescu et al.
2005; Gehart et al. 2010). Insulin and IGF-1 can also recruit the PI3K to the plasma membrane,
triggering its activation by increasing the production of phosphatidylinositol (3,4,5)-triphosphate
(PIP3) from phosphatidylinositol (4,5)-bisphosphate (PIP2) (conversely, Phosphatase and tensin
homolog [PTEN] converts PIP3 to PIP2) and promoting the phosphorylation of Akt on Thr308 by
3-phosphoinositide-dependent protein kinase-1 (PDK 1) and on Ser473 by the mammalian target of
rapamycin complex 2 (mTORC2), also called PDK 2, through acetylation of Rictor (Glidden et al.
2012; Scheid et al. 2002; Sarbassov et al. 2005). These events produce the full activation of Akt, lead-
ing to cell growth and proliferation by a variety of downstream pathways that are involved in promot-
ing cell survival and division. These pathways not only involve the activation of VEGF expression,
which may be regulated by hypoxia-inducible factor (HIF), HIF-1α, signal transducer and activa-
tor of transcription 3 (STAT3), and peroxisome proliferator–activated receptor gamma (PPAR-γ)
(Slomiany et al. 2004; He et al. 2011), but also include the activation of nuclear factor kappa B
(NF-κB) (Mitsiades et al. 2002); the activation of the mTORC1 signaling pathway (Feng 2010; Chen
2011); the inhibition of p53 (Braun et al. 2011; He et al. 2011); the inhibition of Bcl-2-associated
death promoter protein (BAD) and Bcl-2–associated X protein (BAX) (Datta et al. 1997; Matsuzaki
et al. 1999) as well as the activation of cyclin D1 (Yang et al. 2007); and the inhibition of checkpoint
kinase-1 (chK1) (King et al. 2004). Akt also phosphorylates forkhead box O (FOXO) transcription
factors, resulting in nuclear exclusion and enhanced oxidative phosphorylation (Stitt et al. 2004).
The increase in insulin levels inhibits the production of insulin growth factor binding protein 1
(IGFBP-1) and IGFBP-2, leading to a decrease in the circulating levels of IGFBP-1 and IGFBP-2 as well
as an increase in hepatic sensitivity (IGF-1 is mainly produced in the liver) (Brismar et al. 1994). These
changes result in increased circulating levels of IGF-I (Sandhu et al. 2002). Due to their sequence homol-
ogy, IGF-1 is able to interact with the same receptors as insulin; however, IGF-2, which is required for
early development, can interact with its own receptor (IGF-2R) and with IGF-1R (Veronese et al. 2010).
Cancer cells express IGF receptors on their surface and have increased expression of the insulin recep-
tor (Pollak 2012), producing enhanced sensitivity to the circulating levels of IGF-1 as well as insulin lev-
els which may lead to carcinogenesis by enhanced stimulation on the downstream signaling pathways
2.3.2 Chronic Inflammation
Obese people often have chronic low-level, or “subacute,” inflammation, which has been associated
with an increased cancer risk due to the presence of proinflammatory cytokines that are released from
phagocytes and other immune cells; these cytokines infiltrate adipose tissues and contribute to insulin
resistance. Circulating blood monocytes migrate from the vasculature to the extravascular compart-
ments, where they mature into tissue macrophages that infiltrate adipose tissue. Inflammatory factors
such as interleukin 6 (IL-6), IL-17, IL-1β, plasminogen activator inhibitor 1 (PAI1), and tumor necro-
sis factor-alpha (TNF-α) are then released. These macrophages may possess a proinflammatory phe-
notype (Lumeng et al. 2008); infiltration by classically activated macrophages may coincide with the
onset of insulin resistance, which may be produced through the inhibitor of NF-κB kinase β (IKK).
Additionally, alternatively activated macrophages present in lean adipose tissue may play a crucial
role in maintaining the insulin sensitivity of adipocytes via the secretion of IL-10 (Chawla et al. 2011).
These cytokines activate multiple signal pathways linked with carcinogenesis, such as PI3K/
Akt, MAPK, and STAT3. In hepatocellular carcinoma, high levels of TNF and cytokine IL-6,
which are associated with obesity, can transform healthy cells into malignant cells through chronic
low-grade inflammation (Park et al. 2010). TNF and cytokine IL-6 are considered master regulators
of tumor-associated inflammation and tumorigenesis (Grivennikov et al. 2011). They can activate
the Janus-family tyrosine kinases (JAK)–STAT3 and NF-κB pathway as well as the MAPK and
PI3K/Akt pathways. TNF and cytokine IL-6 are also able to activate proliferation via cyclin D1 and
cyclin-dependent kinase 2 (CDK2), which are known cell cycle regulators, thus inhibiting apoptosis
and promoting proliferation and metastasis (Toffanin et al. 2010; Chawla et al. 2011). TNF-α, which
is the best-known member of the TNF family, may contribute to insulin resistance by intervening in
the intracellular insulin signaling cascade (Peraldi et al. 1996; Tzanavari et al. 2010).
Inflammatory cytokines can prevent apoptosis by activating inhibitors of apoptosis (IAPs) as well as
B-cell lymphoma (BCL)-2 family factors. The increased expression of growth factors and of cell adhe-
sion molecules such as vascular cell adhesion molecule 1 (VCAM1) and E-selectin (ELAM1) can stimu-
late metastasis. Furthermore, the expression of matrix metalloproteinases (MMPs), which can increase
microenvironment remodeling phenomena (Khandekar et al. 2011; Chavey et al. 2003), is increased.
PAI1 may also play a role through the increased production of adipose tissue (Wood 2009). As an inhibi-
tor of tissue plasminogen activator (tPA) and urokinase (uPA), PAI1 may act to increase vascularization
in a cooperative synergism with VEGF, which is induced by insulin and IGF (Gallagher et al. 2010).
2.3.3 Leptin, Adiponectin, and Estrogen

Adipocytes secrete the hormones leptin and adiponectin, which are common homeostatic compo-
nents that act as feedback peripheral sensors for the hypothalamus in the control of appetite and
energy expenditure. In the presence of weight gain, increased levels of the hormone leptin released
from adipocytes affect the capacity to conduct negative feedback to the hypothalamus through
their action on central leptin receptor (OBR). Leptin can also interact with peripheral receptors that
are present at lower levels under normal conditions but are increased in breast, prostate, and colon
cancer. Leptin can stimulate the IL-6 receptor, activating JAK/STAT signaling through STAT3
(an oncogenic transcription factor) and concomitantly activating the PI3K/Akt/mTOR axis, which
results in the promotion of invasion and migration (Ghilardi et al. 1996; Li et al. 2008; Wang et al.
2012). Leptin can mediate tumorigenesis in endometrial cancer cells through the JAK2/STAT3,
MAPK/ERK, and PI3K/Akt pathways, leading to the functional activation of cyclooxygenase-2
(COX-2) (Gao et al. 2009). In addition, leptin may act on the fat tissue, which produces excess
amounts of estrogen. Leptin stimulates the expression and activity of aromatase and the transacti-
vation of estrogen receptor-α in breast cancer cells, which has mitogenic and antiapoptotic effects.
High levels of estrogen have been associated with an increased risk of postmenopausal breast and
endometrial cancer; the main source of this estrogen is adipose tissue, through the aromatization
of adrenal androgens (and decreased production of sex hormone–binding globulin) (Catalano et al.
2003, 2004).
The adipokine adiponectin appears to have an opposing role to leptin in cancer development. In
obese individuals, adiponectin levels are usually decreased. Adiponectin may have a role in cancer
due to its possible antiproliferative effects in prostate (Lu et al. 2012) and colon cancer cells (Kim
et al. 2010). Adiponectin acts on a variety of tissues to regulate glucose and lipid metabolism by
binding its receptors ADIPOR1 and ADIPOR2. Many of the effects of adiponectin are mediated by
increasing the conversion of ceramide to sphingosine-1-phosphate (S1P); alterations in sphingolipid
metabolism may modulate tumorigenesis through caspase 8 in a manner that is apparently indepen-
dent of 5′ adenosine monophosphate activated protein kinase (AMP)-activated kinase (AMPK) sig-
naling, which is a key regulator of proliferation in response to nutrient status (Holland et al. 2011);
however, only a few studies have focused on the effects of adiponectin on cancer development.
2.3.4 Microenvironment Changes
As the mass of adipose tissue is increased by the proliferation of adipocyte progenitors in the
stromal–vascular fraction, angiogenesis increases to provide oxygen and nutrients. TNF-α contrib-
utes to this process by increasing the levels of endothelial-immune cell adhesion molecules and
immune trafficking. Leptin secreted by adipocytes plays an important role through the overproduc-
tion and sensitivity of nitric oxide, which in turn leads to angiogenesis. Additionally, the chemo-
kines released from macrophages, stromal cells, and adipocytes as well as changes in endothelial
permeability or endothelial dysfunction and increased levels of hormones enhance the overall pro-
cess. The infiltration of activated macrophages may contribute to tissue invasion, angiogenesis, and
metastasis. Tumor-associated macrophages (TAMs) release macrophage chemoattractant protein
1 (MCP1), which enhances cell infiltration into the tissue; the presence of these factors has been
associated with a poor outcome in some types of cancer (de Visser et al. 2006; Chawla et al. 2011;
Lin et al. 2007).
The tumor microenvironment includes a variety of innate and adaptive immune cells that
can communicate with each other in autocrine and paracrine manners to control tumor growth.
Additionally, these immune cells can communicate with the surrounding stroma, which contains
fibroblasts, endothelial cells, pericytes, and mesenchymal cells, which also appear to have an impor-
tant role in tumorigenesis. The increased hypoxia induces fibrosis mediated by HIF-1α, leading to
hypertrophy with abnormal deposition and accumulation of excess lipids. Hypertrophic adipocytes
release free fatty acids (FFAs), which directly impair endothelial function by activating JNKs,
which, in combination with the cytokines, enhance the production of reactive oxygen species (ROS)
and activate stress signaling pathways, resulting in cell death. Cancer-associated fibroblasts (CAFs)
and preadipocytes are important and also may enhance tumor growth and metastasis (Rutkowski et
Exploring the Variety of Random
Documents with Different Content
udvari vígjátékainknak, hogy akaratlanul is bohózatokká válnak. A
költő nem akar bohózatot írni, de csakhamar bele esik a bohózatos
hangulatba, ki is akarna belőle emelkedni, de ez csak félig-meddig
sikerül s így mind a cselekvény, mind a jellemrajz valami
határozatlan, indokra és stilre nézve egyaránt. A mű a XIV-dik
század elején játszik, III-dik Endre özvegyének udvarában. Az ifjú
Brebir gróf álruhába belopódzik az udvarba, hogy az udvari hölgyek
egyikének, Jusztinnak, a kit szeret s a ki viszont szerette,
szerelméről újabban meggyőződjék. Az ifjú cseh Venczel, választott
magyar király is álruhában jő az udvarhoz, hogy megnyerje Erzsébet
királyleány szerelmét és kezét, de Jusztinba szeret s épen az ál-
Brebir grófra bízza Jusztinhoz írt szerelmes levele átadását. Brebir
gróf kijátszsza a királyt, de ez is visszaadja neki a kölcsönt, mert a
midőn, mint Erzsébet vőlegénye, felfödi kilétét, az ál-Brebir grófot
udvari bolondjává nevezi ki. Ez meg-megtartja a csörgő sipkát, hogy
ellenőrizhesse kedvesét s kijátszhassa a királyt. S csakugyan meg is
nyeri bizalmát s élhiteti vele, hogy Jusztin légyottra hívja. Arra is
ráveszi, hogy a gyanu elkerülése végett az ő udvari bolond ruháját
öltse fel a légyottra. A légyotton Jusztin helyett Deodata, egy vén
udvari hölgy, jelen meg, majd az egész udvar föllép s az ifjú cseh
Venczel csúffá téve, elesik Erzsébet kezétől, Brebir gróf pedig
megnyeri a Jusztinét.
A cselekvényben sok a lelemény, de maga az alap nem igen
erős. Nekünk úgy tetszik, hogy Brebir grófnak teljességgel nincs
szükannyi furfangra, hogy megnyerje kedvese kezét. Házasságukat
semmi sem akadályozza, legfeljebb az, a mit Brebir gróf mindjárt az
expositióban megemlít, hogy őt Jusztin, mint íródiákot szerette meg
s tudni akarná: vajjon hű-e még most is hozzá. De erről mindjárt az
első fölvonásban meggyőződhetett s ha fölfedve rangját, mint kérő
állana elébe, aligha vége nem szakadna az egész vígjátéknak. Az
sem valószínű, hogy Venczel egy ismeretlen ifjúban mindjárt az első
találkozáskor annyira megbízik. Igaz, Venczel nagyon együgyűnek
látszik, csak az a baj, hogy néhol mégis oly ügyes és találékony,
mintha helyette maga a költő szerepelne. Mindamellett a cselekvény
bonyodalma méltánylatot érdemel. Folyvást új meg új fordulattal
emelkedik s érdeket keltő egész a kifejlésig. A jellemrajz már
csekélyebb becsű. A színpad ismert s meglehetősen elkoptatott
alakjaival találkozunk minduntalan, a minők Hancsik, Deodata, sőt
Venczel, Brebir gróf, Jusztin is inkább csak külső, mint benső
érdeket tudnak kelteni. Kevés bennök az élet melege, elevensége; a
jelmez kirívó piperéjében csillognak, s igen is érzik rajtok a színpadi
festék szaga.
Szigligeti munkássága harmadik ágában, a népszínműben sem
volt terméketlen az utóbbi évek alatt. Két népszínművet írt: A strikeot
és az Amerikait,24) a melyek folyvást adatnak, sőt a népszínmű oly
divatossá lőn, mint ezelőtt húsz-huszonöt évvel, a mennyiben ismét
rendes népszínmű-énekesünk és énekesnőnk van, a régibb
népszínművek föleleveníttettek és vasárnaponként a műsor rendes
és kedvencz darabjai. Ez újabb mozgalom nem szült újabb fejlődést
s a kritika is, a mely gyakrabban kezd foglalkozni a népszínművel,
nem épen a legjobb tanácsokat adja a költőknek, mert inkább
zavarja, mint tisztázza a fogalmakat. Mindennap olvassuk, hogy a
népszínmű tárgyában és alakjaiban valami ethnografiainak kell lenni,
a költőnek népszokásokat s mennél kevésbbé ismert
népsajátságokat kell feldolgozni; a népszínmű csak a jelenben
játszhatik, de nem lehet vígjáték, tragikai és komikai vegyületűnek
kell lennie; csak a népnek szabad benne szerepelni más osztályok
kizárásával, még a nagy városi népnek sem, csak a falusinak,
hiszen maga a népszínmű elnevezés eléggé kimagyarázza a válfaj e
sajátságait. De a név nem sokat magyaráz, mert ha a népdal,
népmese, népballada neveket tekintjük, a melyek analogiájára
neveztetett el a népszínmű, egészen más magyarázatot nyerünk. A
népdal, népmese, népballada oly költemények, a melyeket a nép
maga teremt, s a melyeket, ha utánoz a műköltészet, azt szint’ oly
népi vagyis naiv felfogással igyekszik tenni. Vajon a népszínművet a
nép teremti-e? Ellenkezőleg a népnek, vagy színházi nyelven szólva,
a nagy közönségnek írják, s a költő álláspontja nem épen a népi
naivság. A népmese, népballada nemcsak az alsó osztályokkal
foglalkozik, sőt hősei gyakran királyok, várurak, mert a népiesség
nem annyira a tárgyban van, mint a felfogásban. De a népszínmű
nem egy határozott faj neve, mint a tragédia vagy komédia, hanem
több válfajé, a melyeket más nemzetek más névvel neveznek, noha
a németek is használják a Volksstück, Volksdrama kifejezést. Épen
azért jobb a népszínműnek neve helyett fejlődését venni szemügyre
s magából a lényegből magyarázni jellemét s jelölni ki æsthetikailag
jogos határait.
A magyar népszínmű a negyvenes évek elején született s
fejlődése első stádiumán se vígjáték, se bohózat, se dráma, se
tragédia nem volt, de mindebből valami, bizonyos közép faj, vegyes
tartalommal, társadalmi iránynyal, segédűl véve a népdalt és zenét
is. A magyar színköltészetben már volt némi előzménye, külföldi
mintái sem hiányoztak, de legnagyobb hatással volt reá úgy az
európai, mint a magyar politikai, társadalmi és irodalmi viszonyok
democratiai és nemzeti szellemű fejlődése. A tragikomikai elem
többé-kevésbbé mindig megvolt a keresztyén drámában s az
úgynevezett középfajú drámának mintegy alapul szolgált, bár a tárgy
szerint, hol az egyik hol a másik elem túlsúlyával, most a
tragédiához, majd a vígjátékhoz közeledve. A spanyol, angol,
franczia színköltészetben és később a németben is mindig volt egy
csoport válfaj, melyek az idő szelleme szerint különböző
változásokon mentek át. Mi mások Shakespeare közép fajú drámái,
mint a XVIII-dik századéi és ezek mennyire különböznek a jelen
század úgynevezett melodrámáitól és komoly vaudevilleitől. A
regény mindig nagy befolyással volt az e fajú drámára s van még ma
is, úgy szólva az amabból táplálkozik. A harminczas években a
franczia középfajú dráma társadalmi irányt vett, épen mint a regény.
A párisi boulevard-színházak darabjai többé-kevésbbé váddal léptek
föl a társadalom ellen, a socialismus érdekében s kirívó színekkel
festhették az alsóbb osztályok szenvedéseit. A magyar népszínmű is
előszeretettel rajzolta politikai és társadalmi intézményeink hiányait s
a nép szószólója kivánt lenni. Politikai vezérczikkeink fejtegetéseit a
jobbágyság eltörlésétől a börtön-rendszer javításáig örömest fogadta
alapeszméűl s általában ott is, hol nem vett föl valamely speciális
kérdést, részvétet igyekezett kelteni a társadalom alsóbb osztályai
iránt és sokszor igen is kirívóan a fensőbb osztályok rovására.
Politikai életünk democratiai mozgalmainak egyik hatásaként tünt föl
a népszínmű színpadunkon. Ez volt az egyik forrás, melyből merített,
a másikat az irodalom nyújtotta, hol szintén hasonló forrongás
mutatkozott. A fejlődő nemzeti költészet örömest fordult a népies
felé, részint democratiai ösztönből, részint művészi czélból; szorosb
kapcsolatba jött a magyar élettel s nem vetette meg a magyar
genrerajzot. A magyar dalokat nemcsak jambusok- és
trochæusokban írták már s költői rhytmusunk ismét összeolvadt
zenénkkel.
Mindez elősegítette a népszínmű fejlődését. Szigligeti drámai
formába öntötte mindazt, a mi politikai és irodalmi mozgalmainkban
czéljára szolgált. Elődei nyomdokain új utat tört, nem elégedett meg
Kisfaludy komikai genreképeivel, s a mit Munkácsy és Gaal csak
félénken kisértettek meg, a magyar népdal fölhasználását drámai
czélokra, egész bátorsággal érvényre emelte. Eddig csak pár víg
népdalt hallottunk a garaboncziás diák- és Peleskei nótáriusban,
most a víg mellett az érzelmes egész csoportja zendült meg, mint a
drámai mozzanatok kifejezője, vagy kisérője. Szigligeti
népszínművei egész 1848-ig nagy részt középfajú drámák, a
melyekben tragikai és komikai elemek vegyülnek. Köztük a Szökött
katona és A csikós vívták ki a legnagyobb tetszést és méltán, mert
mind cselekvény, mind jellemrajz tekintetében legkitünőbbek.
Azonban a népszínmű sem kerülhette ki a középfajú drámák
örvényét. Gyakran erősb tragikai összeütközéseket használt,
mintsem kiegyenlíthetők lettek volna, a tragikai és komikai elemeket
ritkán vegyítette a tárgy természete és hangulata szerint. Mindig
fölvette a komoly és víg részt, de arra nem igen volt gondja, hogy
ezek egymásnak árthatnak is, gátolhatják egymás fejlődését s
minthogy a víg rész inkább sikerűlt, a legtöbbször háttérbe szorította
a komolyt. Nem a tragikai és komikai vegyületet hibáztatjuk, hanem
annak a módját. Shakespeare tragédiáiba is vegyít némi komikai
elemet, de csak egy pár népjelenetben és csak annyit és úgy, hogy
semmi sem zavarja meg a mű stíljét. Közép fajú drámáiban már
sokkal több van, de nagyrészt az alapeszme, tárgy természetéhez
és hangulatához alkalmazkodik. A magyar népszínműben e két elem
inkább egymás mellett van, mint egymásért, inkább rontja egymást,
mint elősegíti, és együttvéve ritkán æsthetikai hatású.
Ide járult még az is, hogy az énekes rész aránylag nagy tért
foglalt el s nem igen olvadt be a mű szervezetébe. A népszínmű-
énekesnő szerepe, egyénisége miatt ritkán lehetett drámai, néha
nem is volt fontos, de megrontotta a fontosabb szerepeket. A
népszínmű komoly része majdnem oly nemű vázlat volt, mint az
opera-szövegé, s így alig lehetett szó drámai cselekvényről és
jellemrajzról. Az énekes és komikai részek egészen nyakára nőttek a
komoly részeknek s a hatásból az oroszlánrész mindig őket illette.
Látni való volt, hogy e részint össze nem olvadt, részint ily alakban
össze sem olvadható részeknek a fejlődés bizonyos folyamán kell
átmenniök: vagy összeolvadniok, vagy elválalniok. Az énekrészek
nagyobb kiterjedése majd kifejleszti a magyar operettet, a komikai
részek túlsúlya a magyar bohózatot, a komoly rész polgári vagy
népdrámává emelkedik és eldobja a népdalt, vagy ha megtartja is,
mérsékli s egészen czéljához alkalmazza, mint a komolyabb franczia
vaudeville Csak ez lett volna természetes és helyes útja a magyar
népszínmű fejlődésének, hogy nyerjen tartalomban és æsthetikai
becsben. S egy darabig úgy is látszott, mintha ez úton akarna
fejlődni. A forradalom után a viszonyok miatt elvesztvén
irányszerűségét, inkább a komikai conceptio felé hajlott, sőt a
népdalt is inkább alkalmazta tárgyához s igyekezett szervezetébe
olvasztani. Valóban Liliomfi és Dalos Pista a legsikerültebb magyar
bohózatok, kivált az első, a melyet fennebb is kiemeltünk. S
nemcsak Szigligeti indult ez úton, hanem Szigeti is. A magyar polgári
vagy népdráma felé való törekvés sem hiányzott, sőt a magyar
operette terén is tettek kisérletet. Ilyen magyar népdráma Szigligeti
Lelencze, ilyen magyar operette a Debreczeni biró, csakugyan
Szigligetitől. De úgy látszik, hogy mind ez a körülmények
kényszerűségéből folyt s nem a fejlődés belső ösztönéből. A
Lelenczet e legjobb népszínművet, a komoly nemben a népszínmű
énekesnő hiánya szülte, a Debreczeni birót pedig alkalmasint a
zeneszerző nógatása. Ezzel aztán annyiban maradt minden s most
midőn a népszínmű új életre kezd ébredni, nem látunk egyebet, mint
a fejlődés első stádiumának ismétlését csekélyebb tartalommal,
erővel, frisseséggel.
A strike és Amerikai annyiban egészen a régi népszínművekre
emlékeztetnek, a menynyiben a komikai és tragikai elemet nem jól
vegyítik s az énekes részek háttérbe szorítják a cselekvény és
jellemrajz drámai fejlődését. Inkább tárgyukban van valami új, mert a
cselekvény főbb mozzanatai a gyári munkás és kézműves
életviszonyain sarkallanak, a melyekhez Szigligeti eddig nem igen
nyúlt. Némely lap ezt hibáztatta, mintha csikósok és
szegénylegények nélkül nem is lehetne népszínmű. A népszínmű
nem szorítkozhatik csak pusztai vagy falusi élet rajzára, sőt a
fensőbb osztályokat sem zárhatja ki. Hiszen akkor mellőzné a
legérdekesebb összeütközéseket, melyek a különböző osztályok és
egyének viszonyaiból és szenvedélyeiből keletkeznek. A
népszínművet tárgya választásában nem korlátozhatják holmi
önkényes szabályok. Ezt maga a műforma természete szabja meg
épen mint a tragédia és komédiában. De az már csakugyan hibája
mind két műnek, hogy oly viszonyokat tárgyal tragikai felfogással, a
melyek nálunk erre még nem elég alkalmasok, mert a mi
társadalmunkban se a munkás kérdés, se az amerikai párbaj nincs
előtérben.
Mindamellett ezen könnyen túltehetnők magunkat, ha más
tekintetben nyerhetnének kárpótlást. De a legjobb akarat mellett is,
meg kell vallanunk, hogy leginkább csak az énekes és komikai
részleteket élvezhetni bennök. Mindkettő leleménye szegény,
jellemrajza vázlatos és bágyadt, s a cselekvénynek alig van más
érdeme, hogy gyors. A Strikeban Szikráné, a ki csak mellékszemély
s nélküle megtörténhetnék az egész népszínmű, inkább kiemelkedik,
mint István gazda, a mű hőse. Az Amerikaiban Csupri bohózatos
alakja legjobban a többi kopott vagy elmosódott. Megvan bennök a
régibb népszínművek minden árnyoldala, de a fényoldal csak a
szerkezet ügyességében, a technikai készségben nyilatkozik, a mely
ritkán szokta elhagyni Szigligetit.
Egy szóval e két új népszínműben, sőt a régiekhez mérve is a
kevésbbé értékesek között foglal helyet. Nem is hiszszük, hogy a
népszínmű fejlődése a Nemzeti Színházba nagyobb lendületet
vehessen. Itt nincs erre se elég tere, se elég alkalma, se valódi
közönsége. Erre népszínház volna szükséges, hol hamarább és
biztosabban átesnék azon a fejlődési folyamon, a melyet fennebb
érinténk, s a melyet maga Szigligeti is megindított. De fejlődjék vagy
ne fejlődjék, Szigligeti drámaírói pályájának mindig fénypontja
marad. Drámai költészetünket nemzeti alapon egy új válfajjal
gazdagította, a mely nemcsak közönséget vonzott a színházba,
hanem egyszersmind elősegítette politikai és irodalmi átalakulásunk
diadalmas harczait. Azonban mondanánk le a jövő reményéről is?
Előbb-utóbb gyökeret kell verni Pesten egy valódi népszinháznak, s
fejlődnie mindazon válfajoknak, a melyeket most népszínműveknek
nevezünk. E fejlődésnek Szigligeti vetette meg alapját, jelölte ki
irányát s egy pár műve még akkor is élni fog, midőn talán nagyobb
tehetségek a magyar népszínművet a fejlődés és æsthetikai becs
magasabb színvonalára emelik, a mit adjon isten!
1874
A HOLT KÖLTŐ SZERELME.
Ballada Jókai Mórtól. Előadatott a Magyar irók és Művészek estélyén 1874.
E ballada nem jelent meg külön füzetben de mint a magyar irók

és művészek estélyén Liszt zongorakisérete mellett elszavalt
költeményt közölte több lap s általában ugy ünnepelték, mint a
magyar költészet rendkivüli tüneményét. Ime az ok, a miért hozzá
szólunk s nem tartjuk fölöslegesnek vizsgálni: vajon csakugyan
gazdagodott-e költészetünk, vagy az egész zaj csak egyike azon
irodalmi humbugoknak, melyeknek épen nem vagyunk szükében.
Jókai balladájának tárgya Petőfi neje és fia. Nincsenek ugyan
megnevezve, de a költő czélzata nagyon is észre vehető. Nem
vizsgáljuk: ajánlatos-e a nem rég elhunytakat, kiknek rokonai még
élnek, kikhez sok gyöngéd emlék füződik, ily módon regény, dráma
vagy ballada tárgyaivá tenni, s mellőzve egyéb szempontot,
magának a költői hatásnak szempontjából is, nem jobb kerülni
mindent, a mi a kedély elfogultsága miatt épen ugy csökkentheti a
költő szabad alkotását, mint a közönség nyugodt élvezetét! Legyen
elég csak azzal a kérdéssel foglalkoznunk: méltóan énekelte-e meg
Jókai Petőfit, a költőt, a hőst, a jó barátot, s vajon a költemény
mélabus hangjával nincs-e kiáltó ellentétben a conceptio komikai
hóbortossága? Gyönge költeményt irni akár kin megesik, még a
legnagyobb költőn is, de hogy valaki annyira félre ismerje tárgya
természetét s az eredetiséget és hatást abban keresse, a minek sem
eszmei jelentősége, sem æsthetikai értéke nincs, az ugy látszik
Jókainak valóságos irányává kezd válni. Őt annyira túlbecsülte a
közönség és hirlapirodalom, hogy ő maga igen természetes
viszonzásul épen nem becsüli őket s azt hiszi, hogy mindent irhat
nekik, mert mindennel megelégesznek, mindent dicsőitenek a mit ir.
A ballada azon kezdődik, hogy hőse, a költő harczba indul és
bucsuzik neje- és gyermekétől. Ez a balladának legjobb része,
ebben egy pár szép lyrai helyet találhatni, bár csodálkozunk, hogy
Petőfi Szeptember végén czimű elegiáját, mely hasonló érzést,
hasonló rytmusban fejez ki, nem használta fel Jókai, mert igy
erősebben és közvetlenebbűl hatott volna az olvasóra a bucsuzó
költő halálsejtelme. Ez után mind inkább romlik a mű, egy-egy szebb
sor vagy épen versszak igyekszik ugyan fentartani az érdeket, de
mind hiába; a tragikai conceptio csakhamar komikaivá torzul. A hős
ugyanis elesik; a holló a fán megjelenti férje halálát e nőnek, a ki
aztán nem sokára férjhez megy. De a halott nem nyughatik sirjában,
megjelen a nőnek koszorús kalpaggal fején, hanem a fő nem az övé,
valaki másé, egyé a sok közül, a kikkel együtt esett és temettetett el.
Koszoruját meglelte, a fejét nem a mi alkalmasint azt akarná
kifejezni, hogy a költőknek még a sirban is legtöbb gondjok van
koszorújokra. A nő nem ismervén reá, hiába hivja, nem megy vele.
«Te nem vagy ő, férjem sohasem voltál, arczod nem az övé» kiált fel
a nő. Ekkor a szellem – ha ugyan megérdemli e nevet –
mentegetőzni kezd, hogy nem lelte meg fejét, téved a kéz, majd
visszamegy érte s megleli, bár a közös sirban nagyon nehéz a
válogatás. És megjelen ujra, de akkor sem a maga fejével. Húsz
évig jár-fel a sirból más-más fejjel, végre megtalálja a magáét. A nő
ekkor már őszül, a gyermek vén ifjú lett, a ki unja az életet. Most reá
ismernek mindketten s elmennek vele a sirba, hogy örökre
csókolhassák egymást.
Ki nem érzi, a kinek csak egy kis költői érzéke van, hogy Jókai itt
lábbal tapod minden népköltészeti hagyományt, költői illusiót, s a
tragikai conceptiónak a fejkeresés komikai fordulatával oly groteszk
irányt ad, mely ellen egyaránt fellázad erkölcsi és aesthetikai
érzésünk. A népköltészetnek régi hagyománya a sirból feljáró lélek,
a melyet a műköltők nagy hatással szoktak feldolgozni, kivált a
balladaköltők. De e költői motivummal, a mely míndig fönséges, nem
lehet gyermekjátékot űzni. A balladaköltők ezt rendesen mint
subjectiv csodást, mint visiót használják a feldult, lázas lelki állapot
költői kifejezéseül, a minő az erős bánat, kétségbeesés vagy
lelkiismeret furdalása. Ilyenkor mindig az élő kebelében rejlik az a
varázs, a mely a halottat felkelti sirjából s a halott ez érzés ereje által
nyer hatalmat az élő fölött. Az élőnek a halott nem jelenhet meg más
alakban, mint a hogy képzeli, s a halott nem tehet mást az élővel,
mint a mit ez óhajt vagy a mitől fél. Így találjuk ezt az északi, így a
magyar népballadákban, így magának Shakespeare-nek
tragédiáiban is. S ha Jókai e motivumot akarta használni, elég lett
volna, ha a férjhez ment özvegy nem tud boldog lenni uj férje karjai
között, régi férje emléke miatt, ha a sirból feljáró halott vádoló
arczczal mély búval tölti el, ha a gyermeket anyja búja hervasztja s
ha a férj és atya végre magával viszi a boldogtalanokat a sir
nyugodalmába. De Jókai nem kedveli az egyszerűt, a lélektanit, a
költőit, neki valami hallatlan kellett s így teremtette meg a fejét nem
találó halottat, a ki azt húsz évig keresi, tövistől megtépve, elfáradva
a nagy munkában, ruhájaszakadtan. S van-e Jókai e leleményének
bármily tekintetben eszmei jelentősége, van-e kapcsolatban a nő
lelki állapotával s általában fejez-e ki valamit? Ha csakugyan fejez ki
valamit a költő akarata ellenéreis, az nem lehet egyéb, mint parodia
a sirból feljáró szellemekre, épen mint Arany János komikai
cposzában, a Nagyidai czigányok-ban, Puk Mihály esete, a ki
levágott fejét hóna alatt hozza s Csóri, a vajda, azt mondja neki:
«Tedd fel a fejedet, én is voltam olyan szegény ember, mint te.» De
ezt Csóri csak álmodja s különben is a mi illik s igen helyén van egy
komikai eposzban, a mely rendesen a komoly eposzok parodiája
szokott lenni, nemeillik egy tragikai balladába s legkevésbbé Petőfi
emlékéhez.
Petőfi 1848-ban heves polemiát folytatott Jókai ellen és szemére
vetette, hogy «öt impertinentiát» követett el rajta. Nem akarjuk itt
eldönteni, vajon Petőfi vádjai alaposak voltak-e, de hogy Jókai e
balladájával nagy méltatlanságot követett el Petőfi emlékén, az
előttünk bizonyos. Úgy rajzolni Petőfit, mint fejevesztett költőt! Ha a
két költő közül valamelyik csakugyan elvesztette a fejét, az
bizonyára nem Petőfi.
1878
CSIKY GERGELY UJABB SZÍNMŰVEI.
Semmi sem mutatja inkább drámai költészetünk meddőségét,

mint az, hogy Csiky színművei szokatlan figyelemben részesülnek.
Az ifjú költő egymásután nyeri az akadémia drámai pályadíjait; a
nemzeti színház bizonyos előzékenységgel adatja elő minden ujabb
művét; a hirlapoknak épen kedvencze s úgy tekintik őt, mint a jövő
drámaíróját.
Mi elejétől fogva nem tartoztunk Csiky bámulói közé, de értjük e
jelenségeket. Az akadémia Teleki-pályázatán a viszonylag legjobb
műnek mindig kiadatik a díj, a Karácsonyi-díjat csak önálló becsűnek
adhatni ugyan ki, azonban ha nyolcz-tíz évi várakozás után nem
akad kitünő mű, a birálók elvégre oly művet is megjutalmaznak, mely
ha nem kitünő is, de egy vagy más tekintetben önálló becsű. A
nemzeti színház kapva kap minden ujdonságon, a melytől
közönséget remél, különösen Csiky művein, a kit boldogúlt Szigligeti
annyira pártfogásába vett. A hírlapok az akadémia ellenében
fölmagasztalván a Jóslatot, Csiky első művét, s nagy drámaírót
jósolván belőle, már csak következetességből is folyvást dicsérik
kedvenczöket, bár lanyhábban, mint fölléptekor.
Csiky termékenységgel viszonozta a közönség és kritika
figyelmét. A Jóslat után csak hamar két tragédiát írt: a Máguszt és
Jánust s egy vígjátékot, az Ellenállhatatlan czíműt. Mind e művek
fejlődésről tanuskodnak, s bizonyos haladást épen nem tagadhatni
meg Csikytől. Első művében sok mindent összezavart, rosszúl
vegyítette a komoly és komikai elemeket, meséje kuszált és
nehezen érthető volt, a mellékdolgok erőt vettek a főcselekvényen:
újabb műveiben tisztább stilre törekszik, tragédiát és vígjátékot ír,
cselekvénye is kerekebb. Drámai forma, nyelv és verselés
tekintetében is haladt, a mennyiben párbeszédei gyorsabb
menetűek, kevésbbé látszik kedvelni a közhelyeket s olykor
szabatosan és hangzatosan tudja kifejezni gondolatait.
Azonban a drámai ér még most sem fakadt föl benne, s még
folyvást keveset gondol a hagyománynyal, történelemmel, sőt a
valószinűséggel is. Cselekvénye inkább külső, mint belső, inkább
mechanikai csinálmány, mint élő organismus; jellemrajza egy-két
durva vonásból áll, a szenvedély fejlődését, erejét és hangját épen
oly kevéssé képes felfogni, mint visszaadni. Tragikai conceptióiban
maga sem látszik hinni, komikuma pedig csak tréfa, a melynek nincs
semmi mélyebb jelentősége. Általában nem ismeri a külső világot s
belső világa szegény. Mintha nem belső szükségből, hanem külső
kényszerből írna. Nem látszik, hogy valami meghatotta volna. Hiába
keressük az eszméket, s melyek lelkén feküsznek, az érzéseket, a
melyekkel szíve telve. Nem tapasztalatokból, az élet és történelem
átélt vagy átérzett emlékéiből ír, hanem olvasmányokból s a
képzelődés ködképeiből. Innen cselekvényében nincsen élet
alakjaiban elevenség. Nem annyira természetesen alkot, mint
erőszakosan combinál, élő emberek helyett elvont forgalmakat
mozgat, s minthogy nincs leleményes phantaziája, erőszakolja a
bonyodalmat és lélektani absurdumokba téved. Érzéke levén a
drámai forma iránt, s némi technikai ügyességet sajátítván el,
könnyen önti drámába a mit így kigondolt. S azok szemre-főre
mutatnak is valamit, de belől üresek, s a legjobb esetben is hidegen
hagyják a szívet.
A Mágusz egy felvonásos tragédia.25) Egy felvonásban jó

tragédiát írni nehéz, majdnem lehetetlen. Bármely jó tárgy megromlik
így összeszorítva, mert nincs hely érdekes bonyodalom szövésére s
a szenvedély fejlődésének rajzára. Más a vígjáték, a hol egy
felvonásba könnyen szoríthatni egy kis komikai összeütközést, sőt
vannak tárgyak, a melyek az egy felvonást úgyszólva követelik. Egy
kis vígság elmulathatja az embert, de egy kis szomorúsággal nem
elégszünk meg, a nagy szomorúság pedig kicsinynyé törpítve
hatástalan. Midőn részvétet, félelmet, szánalmat és megnyugvást, a
tragikum ez alkatrészeit, egy pár negyed óra alatt kell átéreznünk, az
lesz belőle, hogy egyiket sem érezhetjük át egészen. Az életben is
örömest nevetünk egy jó tréfán nehány perczig s aztán dolgunk után
látunk, de ha igazán meg vagyunk hatva, s ki akarjuk sírni
magunkat, arra több idő kell. Csiky nemcsak azzal gyöngítette műve
tragikai hatását, hogy egy nagy tárgyat összeszorított, hanem azzal
is, hogy hőse iránt nem tudott részvétet gerjeszteni.
Ki az a gittoni mágusz, a kit Simonnak neveznek? Úgy látszik
titkos keresztyén, a ki csak színleg űzi szemfényvesztő mesterségét,
egészen át van hatva az új hittől s azt az egész római birodalomban
el akarja terjeszteni. Hogy titkolja másoktól keresztyén hitét, az
érthető, de hogy nekünk nézőknek sem vallja be, az egy kissé
különös. Egy határozott nagy czél, a melyet értünk, inkább fog iránta
érdeket kelteni, mint a homályos beszéd, a melyből tisztán ki nem
vehető, hogy tulajdonkép minő hitért küzd, a Krisztus hiteért-e vagy
maga egy új Krisztus. S mi által reméli elérni nagy czélját? Azzal,
hogy magához vesz egy tyrusi utcsai leányt, a ki szakasztott mása
Nero meghalt kedvesének, Phoebenek, s azt úgy szándékszik kiadni
Nerónak, mint máguszi mesterség által halottaiból feltámasztott
kedvesét, a miért őt Nero pontifex maximussá fogja emelni. Ime
Simon nagy czélja, a melyért föláldozza szerelmét, mert a leányt ő is
szereti, bár e föláldozásból sokat levon az, hogy szerelmét nem hiszi
viszonzottnak. De vajon Nero elhiheti-e, hogy Helena csakugyan a
föltámasztott Phœbe? Hiszen ha beszélni fog vele, könnyen
meggyőződhetik az ellenkezőről, mert Helena semmit sem tud a
múltról. De ha Nero Phœbe helyett megelégszik egy hozzá hasonló
leánynyal is, és Simont pontifex maximussá emeli, vajon el fogja-e
tűrni az új vallást, s ha ő eltűri is, eltűri-e Róma? Nem lábbal
tapodása ez úgy a valószinűségnek, mint a történelmi hűségnek s
vajon oly hígvelejű ember iránt, minő Simon, érezhetünk-e tragikai
részvétet?
Bizonyára a tragikai hős vagy czéljában vagy eszközeiben mindig
tévedő s ellenkezésbe jő a fennálló renddel, de mind czéljának, mind
eszközének olyannak kell lenni, a melyet érthessünk, a melybe
hihessünk, a mely bizonyos sikerre számíthat, annyira, hogy hasonló
körülmények között talán magok a nézők is hasonlóan
cselekednének. Ha minden tévedés tragikai, akkor a félkegyelmű
emberek épen oly tragikai hősök, mint a Coriolanok és Brutusok. De
a Mágusz tragikai alapjának még más baja is van. Úgy látszik, hogy
Simon fölhagyna nagy czéljával, ha tudná, hogy Helena őt szereti,
legalább azt mutatja a Helena és Simon közti utolsó jelenet. A
költőnek tehát úgy kellett volna rajzolnia Helenát, hogy Simon csak a
kifejtésnél vegye észre szerelmét, vagy Simont úgy, hogy egy
darabig legyőzi szerelmét, de az később erőt vesz rajta. De e helyett
Helena már az első jelenésben úgy beszél, hogy Simon könnyen
észrevehetné hajlamát. A mily könnyen bánik el Csiky a lélektani
mozzanatokkal, ép oly kevés gondja van a korrajzra. Az összes
személyzet úgy beszél mintha keresztyén volna, s midőn a mű
végén Nero föllép, épen nem ismerünk a történelem Nerójára. A
kegyetlen Nero itt oly kegyelmes, bölcs, mintha Simon már rég
megtérítette volna.
Janusban,26) a mely öt felvonásos tragédia, szintén a pogányság

és keresztyénség közti küzdelmet rajzolja Csiky, csakhogy itt nem a
római, hanem a magyar pogánysággal foly a küzdelem. A míg a
Máguszban a pogányok is keresztyén szinezetűek, itt a pogányság
túlnyomó, kivéve magát Janust, a pogányság fejét, a ki oly jámbor
ember, hogy keresztyénnek is beillenék, ellenben a keresztyének oly
jóindulattal viseltetnek pogány honfitársaik iránt, hogy nem volna
nehéz őket visszatéríteni. A mű tele van pogány táltossal és
jósnővel, azonban keresztyén papnak se híre, se hamva, mintha
ezek részt sem vettek volna a küzdelemben. De nemcsak ebben vét
Csiky a történelmi hűség ellen. A mint I. Béla királyt rajzolja és
megindítja a cselekvényt, az már a soknál is több. I. Bélát, az
erélyes királyt, a ki egész gondját a keresztyénség megszilárdítására
fordította, úgy rajzolja, mint a ki vadászsza a pogány magyarok
barátságát, meglátogatja vezéröket, Janust személyesen hívja meg
az országgyűlésre, mindenkép igyekszik megnyerni őt és párthíveit a
közjó érdekében, sőt meg is esküszik előtte, hogy az ősmagyar hitet
sohasem fogja bántani.
Én Béla, a magyar nemzet királya

Királyi szóm kötöm le s esküszöm,
Hogy téged, Janus s a tiéidet
Hitedben, ős szokásaidban soha
Nem foglak háborítni, bántani;
S mindenki ellen, bárki légyen az,
Királyi kardom lesz az oltalom!
Hanem legyünk elnézők s fogadjuk el a szerző álláspontját, a

mely nemcsak történelmileg valótlan, hanem lélektanilag sem
valószinű. Hiszen az újabb drámaírók úgy is hozzászoktattak
bennünket a történelemellenes történelmi drámához s ha láttuk
Miltont, a ki a legélesb ellentéte az író és államférfiu Miltonnak, ha
elfogadtunk a hagyományos Iskariót helyett egy egészen képzelt
ifjonczot, miért ne fogadhatnánk el egy pogánybarát Béla királyt s
egy keresztyén jámborságú Janust, a kik atyafiságosan kiegyeznek.
Ez alapon mi lehetne természetesb fejlemény, mint az, hogy a két
kibékült ellentétes irány mindinkább összeütközik; a viszonyok és
szenvedélyek kényszerűségénél fogva, a király és Janus akaratlan is
esküszegőkké válnak és végre Janus elbukik nem azért, mert
megszegte eskűjét, hanem mert ki nem egyenlíthető dolgokat akart
összebékéltetni s a keresztyénség ellen támadva, elvégre is az
ősvallást törekedett visszaállítani, a melynek nincs jövője. A vallásos
és politikai összeütközéseket éleszthette volna a szenvedélyeké, a
mire elég anyag van azon körülményben, hogy Janus leánya. Ara,
bele szeret egy keresztyén lovagba, elszökik vele és keresztyénné
lesz.
Azonban Csiky nem a viszonyok és szenvedélyek
összeütközéséből indítja meg a bonyodalmat, hanem
cselszövénynyel idézi azt elő, melynek a politikai és vallásos eszmék
és szenvedélyek küzdelmében csak mellékesen lehet helye. Ő ezt
teszi fővé s Janus tulajdonkép csak báb Rasdi jósnő és meghitte.
Karvaly, kezében, a kik egy kissé durva furfanggal mindent
elkövetnek, hogy megtörténjék az, a mi különben is bekövetkezhetett
volna s elhitessék Janussal, hogy mindez a hitszegő Béla király
műve. E cselszövők tudniillik Boleszlót éjjel titkon Arához vezetik
légyottra, bár nincs szükség reá, mert Boleszló különben is
látogathatja a leányt, elősegítik elszöktetését és áttérését a
keresztyén hitre s midőn Janus visszahozza Arát várába, szintén ők
eszközlői újabb szökésének. E mellett föllázítják a keresztyének
ellen pogány társaikat s midőn már minden készen van, nógatják
Janust, hogy álljon boszút szenvedett sérelmeiért s tűzze ki az őshit,
a lázadás zászlóját. De majdnem kudarczot vallanak, mert Janus
egyik nőcseléde elárulja Karvalyt, elmondja, hogy kezdettől fogva ő
volt biztosa Boleszlónak, ő vezette Arát a keresztyén papokhoz, ő
segítette elő újabb elszökésöket is, s hazugság mindaz, a mivel
Janust ámítja. Erre Janus leszúrja Karvalyt, a ki aztán a jósnő
biztatására haldokolva azt hazudja, hogy az egész ármányt Béla
király szőtte s ő az oka minden szerencsétlenségnek. És Janus
Karvalynak, a kit azelőtt egy pár perczczel épen hazugságáért szúrt
le, most minden újabb hazugságát elhiszi s kitűzi a lázadás
zászlaját, sőt akkor sem vonja vissza azt, midőn Béla király megjelen
nála, s visszahozva leányát, elmondja, hogy minden tudtán kívül
történt, s a bűnösöket megbünteti. Bánkódik ugyan egy kissé,
hanem aztán annál nagyobb hévvel kezdi rábeszélni a királyt, hogy
térjen vissza az őshitre s álljon a pogány magyarság élére. Béla
visszautasítja az ajánlatot, s kitör a polgárháború. Janus elveszti a
csatát, s őt magát is megtöri most párthívei aljassága, majd leánya
halála; megszállja a lelkiismeret is, nem akar tovább küzdeni s
visszautasítva a király ajánlatát, a ki megkegyelmez neki, ha
keresztyén hitre tér, egy tőrszúrással véget vet életének.
Ime Rasdi és Karvaly cselszövényéből mily nagy forradalom
támadt. Nélkülök talán még ma is békén élne együtt
Magyarországban keresztyén és pogány a haza üdvére. De fogadjuk
el alapul e cselszövényt is, vajon akkor is összhangzásban van-e az
Janus jellemével, s így elhihető-e sikere? Könnyenhivő,
szenvedélyes ember-e Janus? Épen nem; mérsékelt, nyugodt,
mindent megfontoló. Viseltetik-e Rasdi és Karvaly iránt némi kiváló
rokonszenvvel és bizalommal? Nem, sőt úgy látszik, hogy Béla király
az, a kit különösen tisztel, s a kiben leginkább bízik. Hogy ily
cselszövény kifoghasson rajta, egészen máskép kellett volna rajzolni
őt. Csiky nem igen látszik érteni, hogy a jellemrajz és cselekvény
mily benső kapcsolatban vannak egymással és egymást szülve és
táplálva alkotják a dráma organismusát. A legjobb cselekvény, a
legerősb indokok elvesztik hatásukat, ha a jellemrajzzal
ellenkezésbe jönnek. Például Othello egész cselekvénye megromlik,
sőt nevetségessé válik, ha Othello jelleme nem táplálja a fejlődést.
Egyébiránt Janus jellemrajza nem egyéb hideg abstractiónál, s
annak is hibás. Szegényes és nyomorék alak, itt-ott fölcziczomázva
Brutus, Bánk bán s a trónkereső Borics rongyaival Többé-kevésbbé
a többi személyek is ilyenek.
Mindamellett a műnek van méltánylandó oldala is. Ha Csiky nem
tudott tragikai hőst rajzolni, legalább tragikai alapot keresett; ha
jellemrajzában és cselekvényében nincs történelmi hűség, lélektani
igazság, benső élet, költői elevenség, legalább a cselekvény kerek,
mely folyvást halad, emelkedik és siet a kifejlés felé. Ha nyelve nem
drámilag jellemző, legalább nem szószaporító s épen nem hiányzik
benne a külső drámaiság. Általában Csikynek sok érzéke van
drámai forma iránt s hogy e tekintetben folyvást halad, mutatja
legújabb vígjátéka is.
Valóban az Ellenállhatatlan27) czímű három felvonásos

vígjátékának főbecse a tiszta drámai formában, kerek
cselekvényben s a kidolgozás bizonyos széparányúságában áll. Ha
a tartalom: a jellemrajz és cselekvény benső értéke megfelelne a
forma szabatosságának, az Ellenállhatatlanban kitünő vígjátékot
bírnánk. De a belsőt nem lehet úgy elsajátítani, mint a külsőt. A
külsőt inkább a tanulmány és gyakorlat nyújtja, a belsőt inkább az
élet, ha van szemünk látni a látnivalót, s ha van elég erőnk azt
átalakítva visszasugározni a phantasia tükrében. Csiky, a mint már
megjegyeztük, keveset merít az élet tapasztalataiból, a kedély benső
világából s nagyrészt csak olvasmányait dolgozza föl, inkább
combináló, mint alkotó tehetséggel. Jelen művében Moreto Szép
Diegójából átvette a főalakot s egy új cselekvényt gondolt hozzá,
mely egységes és kerek ugyan, de majdnem oly szegény, mint nem
valószinű. Leleményre nézve több mint Janus, jellemrajza sem oly
ellenmondó, alakjai is tetszetősbek, de egyaránt érezhetni benne az
élet és költészet elevenségének hiányát. Ide járul még, hogy a mű a
fensőbb, a jellemvígjáték követelésével lép föl, különösen a külső
forma és nyelv tekintetében s tulajdonkép nem is annyira bohózat,
mint valóságos operetteszerű mű, a jobb operettek hegyke, de találó
vonásai s derült frissesége nélkül. A forma és tartalom e
meghasonlása sokat árt a mű hatásának, a színészt is zavarba
hozza, a közönséget is, is egyik sem adhatja át magát valamely
határozott hangulatnak, a mely oly könnyen szokta illusióba ringatni
az embert.
A vígjáték Spanyolországban történik. A mióta Rákosi és Dóczi
fölfedezték Spanyolországot, vígjátékíróink örömest vándorolnak e
szép országba, a hol minden lehetetlenség megtörténhetik.
Asturiában vagyunk. Diego regens és gyám férjhez akarja adni a
herczegnőt, Florindát, de nem mondja meg nekik, a miből Florinda
és dajkája azt következtetik, hogy maga akarja elvenni. Pedig
Florinda Roland herczeget szereti, a ki a mórok ellen harczol, kit
szeretne értesíteni bújáról és segítségül hívni. Ime a mű kiinduló
pontja. Egy regens, egy gyám nem mondja meg herczegnőjének,
hogy kit szánt férjeül, egy leány, ki nem tudakolja, hogy kihez akarják
férjhez adni. Ezt bizony bajosan hiszi el valaki még
Spanyolországban is. De hát miért nem mondja meg Diego a férj
nevét? Azért, mert heves természetű, a ki senkit nem enged szóhoz
jutni. Ez nem baj, annál többet beszélhet maga, annál inkább
elmondhatja, hogy ki a választott vőlegény. S azt hogyan veszi
fejébe a herczegnő, hogy gyámja akarja elvenni? Valamely
félreértett czélzásából talán vagy magaviseletéből? Épen nem. Egy
szóval a szerző úgy akarja, hogy Florinda aggódjék és segítségül
hívja kedvesét. De kitől küldjön neki levelet? A dajka Rodrigo kóbor
lovagot ajánlja, a ki komája, Gil Perez vendéglőjében szállásol s igen
szegény ördög. Ez egy hiú, képzelgő ember, a ki ellenállhatatlannak
tartja magát, s mert a herczegnő és dajkája a templomból jövet
szemügyre veszik, azt hiszi, hogy Florinda beleszeretett. S
csakugyan hivatja is. Rodrigónak igen viseltes ruhája levén, jobb
után látna, de se pénz, se hitel. Azonban Dorido kóbor lovagtársa
elmondja Rodrigo herczegi szerencséjét kedvesének, a vendéglős
leányának, ez atyjának, a ki mindjárt harmincz aranyat kölcsönöz
neki, remélvén, hogy a bérlett vendéglő a herczegnő kegyéből majd
tulajdonába megy.
Ez a vígjáték másik kiinduló pontja, a melyet szintoly kevéssé
hihetni, mint az elsőt. Hogy az udvarból senkit sem küldhet a
herczegnő kedveséhez, azt még érthetni, de hogy az egész
városban, ne találkoznék senki ismerős, a ki jó pénzért a levelet
elvinné Roland herczeghez, ez kevésbbé hihető. Azt is bajos elhinni,

PDF Inflammation Oxidative Stress and Cancer Dietary Approaches for Cancer Prevention 1st Edition Ah-Ng Tony Kong download

Uploaded by

Copyright:

Available Formats

PDF Inflammation Oxidative Stress and Cancer Dietary Approaches for Cancer Prevention 1st Edition Ah-Ng Tony Kong download

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

PDF Inflammation Oxidative Stress and Cancer Dietary Approaches for Cancer Prevention 1st Edition Ah-Ng Tony Kong download

Uploaded by

Copyright:

Available Formats

Download the full version of the ebook at ebookfinal.

Inflammation Oxidative Stress and Cancer Dietary

Download more ebook instantly today at https://ebookfinal.com

Prevention of Cancer The Biology of Cancer 1st Edition

Skin Cancer Prevention 1st Edition Ringborg Ulrik

Nutraceuticals in Health and Disease Prevention Oxidative

Epigenetics of Cancer Prevention 1st Edition Anupam

Hypermodels in Mathematical Finance 1st Edition Siu-Ah Ng

Lung Cancer Prevention Management and Emerging Therapies

Inflammation and Cancer Methods and Protocols Volume 2

Inflammation and Cancer Methods and Protocols Volume 2

Boca Raton London New York

CRC Press is an imprint of the

© 2014 by Taylor & Francis Group, LLC

No claim to original U.S. Government works

International Standard Book Number-13: 978-1-4665-0371-7 (eBook - PDF)

and the CRC Press Web site at

For my father, Kong Yuk-Ming, and my mother,

Section I Inflammation, Oxidative Stress, Nutritional

Chapter 1 Overview on Oxidative Stress, Inflammation, Cancer Initiation/Progression,

Chapter 2 Overview of Obesity, Inflammation, and Cancer........................................................ 21

Chapter 3 Inflammation-Induced Esophageal and Colon Adenocarcinoma Formation in

Chapter 4 Overview of Common Dietary Phytochemicals Possessing Antioxidant

Chapter 5 Signal Transduction and Molecular Targets of Dietary Cancer-Preventive

Chapter 6 Biomarkers for Diet in Cancer Prevention Studies................................................... 107

Chapter 7 Metabolism and Transport of Anticancer and Anti-Inflammatory

Chapter 8 Pharmacokinetics of Dietary Isothiocyanates and Flavonoids................................. 171

Chapter 10 Vitamin D and Inflammation in Cancer: Emerging Concepts..................................205

Chapter 11 Vitamin E Family of Compounds and Cancer Prevention........................................ 221

Chapter 12 The Protective Role of Vitamin E in Inflammation and Cancer............................... 247

Section V Omega-3 and Omega-6 Fatty Acids

Chapter 14 Plant and Marine Sources of Omega-3 Polyunsaturated Fatty Acids,

Chapter 15 Polyunsaturated Fatty Acids and Cancer Prevention................................................ 299

Chapter 16 Anti-Inflammatory and Proresolving Effects of Docosahexaenoic Acid:

Section VI Flavonoids and Polyphenols

Chapter 17 Green Tea and Cancer Prevention............................................................................. 331

Chapter 18 Curcumin from Turmeric Spice, Anti-Inflammatory and Antioxidant

Chapter 19 Flavonoids: Impact on Prostate Cancer and Breast Cancer...................................... 355

Chapter 20 Cancer Prevention by Isoflavone............................................................................... 387

Chapter 21 Anti-Inflammatory Efficacy of Silibinin: Role in Cancer Chemoprevention........... 401

Chapter 22 Cancer Prevention by Antioxidant Compounds from Berries.................................. 419

Chapter 23 Garlic and Cancer Prevention................................................................................... 435

Chapter 24 Molecular Mechanisms of Cancer Chemoprevention with Benzyl Isothiocyanate..... 447

Chapter 25 Suppression of Prostate Carcinogenesis by Dietary Isothiocyanates........................ 463

Chapter 27 Chemoprevention of Lung Cancer by Ginseng......................................................... 495

Chapter 28 Anti-Inflammatory Botanical Dietary Supplements for Women’s Health:

Chapter 29 PHY906, a Cancer Adjuvant Therapy, Differentially Affects Inflammation of

Section IX Epigenetics and Chronic Inflammation

Chapter 31 Epigenetic Modifications by Dietary Phytochemicals in Cancer Prevention........... 577

Chapter 32 Nutritional Phytochemicals and the Management of Chronic Inflammation........... 589

Aamir Ahmad Barrie R. Cassileth

David Coleman Ming Hu

Birgit M. Dietz Zaoli Jiang

Ah-Ng Tony Kong Yong Ma

Dan Peiffer Limin Shu

Anuradha Sehrawat Gary D. Stoner

Janel Suburu Alpna Tyagi

Lilian U. Thompson Ashleigh K. A. Wiggins

Richa Tiwary Shizuo Yamada

Guang-Yu Yang Weiping Yu

Section I Inflammation, Oxidative Stress, Nutritional

1.2 CHEMICAL CARCINOGENS AND THEIR METABOLIC ACTIVATION

1.2.1 Metabolic Conversion of Chemical Carcinogens

1.2.2 Classes of Carcinogenic Chemicals

1.2.2.2 Heterocyclic Aromatic Amines

1.3 ROS/REACTIVE NITROGEN SPECIES

1.3.1 Defenses against Oxidative Stress

1.3.3 Dietary Phytochemicals Targeting Nrf2/Keap1 Signaling

1.6 PERSPECTIVE AND CONCLUSION

2.2 OBESITY AND CANCER RISK

2.2.2 Endometrial and Colorectal Cancers

2.2.3 Esophageal and Pancreatic Cancers

2.2.4 Kidney and Prostate Cancers

2.2.5 Others Types of Cancer

2.3.1 Insulin and IGF-1

2.3.3 Leptin, Adiponectin, and Estrogen