Phytochemicals in Cancer Treatment From Preclinical Studies To Clinical Practice

REVIEW
published: 28 January 2020

doi: 10.3389/fphar.2019.01614
Phytochemicals in Cancer Treatment:

From Preclinical Studies to Clinical
Practice
Amit S. Choudhari 1, Pallavi C. Mandave 2, Manasi Deshpande 3*, Prabhakar Ranjekar 4
and Om Prakash 5,6
1 Combi-Chem Bio-Resource Center, Organic Chemistry Division, CSIR-National Chemical Laboratory, Pune, India,
2 Interactive Research School of Health Affairs, Bharati Vidyapeeth Deemed University, Pune, India, 3 Department of
Dravyaguna Vigan, Ayurved Pharmacology, College of Ayurved, Bharati Vidyapeeth Deemed University, Pune, India,
4 Innovation Biologicals Pvt. Ltd., Pune, India, 5 Department of Microbiology, Immunology and Parasitology, Louisiana State
University Health Sciences Center, New Orleans, LA, United States, 6 Stanley S. Scott Cancer Center, Louisiana State
University Health Sciences Center, New Orleans, LA, United States
Cancer is a severe health problem that continues to be a leading cause of death worldwide.
Increasing knowledge of the molecular mechanisms underlying cancer progression has led to
the development of a vast number of anticancer drugs. However, the use of chemically
Edited by:
synthesized drugs has not significantly improved the overall survival rate over the past few
Salvatore Salomone, decades. As a result, new strategies and novel chemoprevention agents are needed to
University of Catania, Italy
complement current cancer therapies to improve efficiency. Naturally occurring compounds
Reviewed by:
from plants known as phytochemicals, serve as vital resources for novel drugs and are also
Tin Khor,
Emergent Biosolutions, sources for cancer therapy. Some typical examples include taxol analogs, vinca alkaloids such
United States as vincristine, vinblastine, and podophyllotoxin analogs. These phytochemicals often act via
Ioana Berindan Neagoe,
Iuliu Hațieganu University of Medicine
regulating molecular pathways which are implicated in growth and progression of cancer. The
and Pharmacy, Romania specific mechanisms include increasing antioxidant status, carcinogen inactivation, inhibiting
*Correspondence: proliferation, induction of cell cycle arrest and apoptosis; and regulation of the immune system.
Manasi Deshpande
The primary objective of this review is to describe what we know to date of the active
[email protected]
compounds in the natural products, along with their pharmacologic action and molecular or
Specialty section: specific targets. Recent trends and gaps in phytochemical based anticancer drug discovery
This article was submitted to
are also explored. The authors wish to expand the phytochemical research area not only for
Experimental Pharmacology
and Drug Discovery, their scientific soundness but also for their potential druggability. Hence, the emphasis is given
a section of the journal to information about anticancer phytochemicals which are evaluated at preclinical and
Frontiers in Pharmacology
clinical level.
Received: 13 September 2019
Accepted: 10 December 2019 Keywords: phytochemicals, anticancer, preclinical, clinical, medicinal plants
Published: 28 January 2020
Citation:
Choudhari AS, Mandave PC,
Deshpande M, Ranjekar P and
INTRODUCTION
Prakash O (2020) Phytochemicals in
Cancer Treatment: From Preclinical
Cancer is a major public health problem that has a significant global impact on both developed and
Studies to Clinical Practice. developing countries. In 2018, an estimated 18.1 million new cases of cancer occurred worldwide
Front. Pharmacol. 10:1614. which are likely to increase to 23.6 million new cases each year by 2030 (Bray et al., 2018).
doi: 10.3389/fphar.2019.01614 Considering the high profile nature of the disease, its treatment has been a constant struggle with
Frontiers in Pharmacology | www.frontiersin.org 1 January 2020 | Volume 10 | Article 1614

Choudhari et al. Phytochemicals in Cancer Treatment
relatively less success. Currently available options for cancer transferred verbally from one generation to the next generation.
treatment involve surgical removal and radiation treatment of The folklore system has documented all parameters about the
the large accumulated biomass of cancer, typically followed by drugs and their specific uses in the disease conditions. These
systemic chemotherapy treatment for maintenance. The drugs were prepared as tinctures, teas, powders, poultices,
primarily available chemotherapeutic agents include decoctions, and other types of formulations (Ogbonna et al.,
antimetabolites (e.g., methotrexate), DNA-interactive agents 2012; Fridlender et al., 2015) which were the most common
(e.g., cisplatin, doxorubicin), anti-tubulin agents (taxanes), methods of drug preparation until 18th century. Unfortunately,
hormones, and molecular targeting agents (Nussbaumer et al., none of them could fit into the modern scientific definition of
2011). The major disadvantages of chemotherapy are recurrence a drug.
of cancer, drug resistance, and toxic effects on non-targeted With advances in organic chemistry and chemical analysis,
tissues that can restrain the use of anticancer drugs and thus an analytical investigation of active components of medicinal
impair patient’s quality of life. To overcome the problems of plants and herbal remedies was pursued in late 18th or early
present therapy, search for new promising anticancer agents with 19th centuries, which opened the doors toward the isolation/
better efficacy and lesser side effects continues. purification and characterization of numerous active
Phytochemicals and derivatives present in plants are principles of plants. This increased the pace of drug
promising options to improve treatment efficiency in cancer discovery and led to a miracle innovation in the medical
patients and decrease adverse reactions. A number of these field. The first breakthrough which launched the first
phytochemicals are naturally occurring biologically active generation of drugs came with the isolation of analgesic
compounds with significant antitumor potential. The (pain killing) drugs morphine from the plant Papaver
development of effective and side-effects free phytochemical somniferum. Later, many well-defined 20 th century drugs
based anticancer therapy begins with the testing of natural were derived from plants, including salicylic acid, the
extracts (from dry/wet plant material) for potential anticancer precursor of aspirin (Salix sp.), cocaine (Erythroxylum coca),
biological activity followed by purification of active quinine (Cinchona officinalis), digitoxin (Digitalis purpurea
phytochemicals based on bioassay-guided fractionation and and Digitalis lanata), and many others with pharmaceutical
testing for in vitro and in vivo effects. In the present review, an and clinical potential (Newman et al., 2000; Butler, 2004;
attempt has been made to gather information specifically about Ogbonna et al., 2012). Over the period from around 1981 to
the anti-cancer phytochemicals that are evaluated at preclinical the end of 2014, more than half of all approved small‐molecule
and clinical levels as well as those available in the market, until drugs originated from natural products, where they served as
now. In preclinical section, we have reviewed the phytochemicals drug precursors, templates for synthetic modification, and
with a reported in vivo activity. This review further highlights pharmacological probes (Newman and Cragg, 2016). This in
phytochemicals which are assessed at preclinical level and also itself demonstrates the enormous medicinal potential of plants
mentions some phytochemicals which are in the clinical trials that has been known for thousands of years in traditional
along with the brief information on the presently used plant- medicine. A few commercially available plant-derived
based anticancer drugs. compounds used against various diseases are listed in Table 1.
PLANT DERIVED DRUGS: A HISTORICAL PHYTOCHEMICALS WITH ANTICANCER

PERSPECTIVE PROPERTIES
Plants have been used to treat various disease aliment from time Scientific evidences indicate that phytochemicals have significant
immemorial. Ayurveda, Traditional Indian Medicine (TIM), and antitumor potential. Approximately, 50% of approved anticancer
the Traditional Chinese Medicine (TCM) remain the most drugs from 1940 to 2014 originate from natural products or
ancient (4500 BC) yet living traditions. In the ancient period, directly derived therefrom (Newman and Cragg, 2016). Some of
the knowledge of selection of right plants, a specific time for their the remarkable anticancer phytochemicals in this regard are
collection, method of drug preparation with their specific use was describe in the present review. These phytochemicals have
TABLE 1 | List of commercially available plant derived drugs on various diseases.
Drug Class of drug Plant source Disease Reference
Apomorphine Dopamine receptor agonist Papaver somniferum L. Parkinson (Deleu et al., 2004)
Arteether Sesquiterpene trioxane lactone Artemisia annua Malaria (van Agtmael et al., 1999)
Galantamine Amaryllidaceae alkaloid Galanthus woronowii Alzheimer (Heinrich and Lee Teoh, 2004)
Nitisinone Mesotrione Callistemon citrinus Hepatorenal tyrosinemia (Das, 2017)
Paclitaxel Taxane diterpene Taxus brevifolia Nutt. Cancer (Wani et al., 1971)
Tiotropium Muscarinic receptor antagonist Atropa belladonna Asthma and COPD (Mundy and Kirkpatrick, 2004)
COPD, chronic obstructive pulmonary disease.

been tested for anti-cancer efficacy at both in vitro and in vivo lymphoma 2 (Bcl-2), while upregulating Bcl-2-associated X
levels. They possess complementary and overlapping (Bax) protein (Chen et al., 2018). Subsequent studies, showed
mechanisms to slow down the carcinogenic process by that allicin (5 µM) altered TIMP/MMP balance, via reducing the
scavenging free radicals (Lee et al., 2013), suppressing survival activity of the PI3K/AKT signaling pathway thereby significantly
and proliferation of malignant cells (Yan et al., 2018), as well as inhibiting adhesion, invasion, and migration of lung
diminishing invasiveness and angiogenesis of tumors (Lu et al., adenocarcinoma A549 and H1299 cells (Huang et al., 2017).
2018a). They exert wide and complex range of actions on Alpinumisoflavone (AIF) is a pyranoisoflavone found in
different molecular targets and signal transduction pathways Derris eriocarpa (Leguminosae) plant. In BALB/c nude mice
including membrane receptors (Deng et al., 2017), kinases xenograft with human clear cell renal cell carcinoma (ccRCC)
(Dou et al., 2018), downstream tumor-activator or -suppressor cell xenografts, AIF (40 mg/kg) suppressed growth, and
proteins (Adams et al., 2010), transcriptional factors (Zhang metastasis of 786-O human ccRCC cells. The inhibitory effect
et al., 2017b), microRNAs (miRNAs) (Cojocneanu et al., 2015), was due to increase expression of miR-101 by suppressing Akt
cyclins, and caspases (Yan et al., 2018). signaling (i.e., decreasing RLIP76 expression and p-Akt/t-Akt
ratio) (Wang et al., 2017). In addition, AIF was reported to
increase radiosensitivity in esophageal squamous cell carcinoma
PHYTOCHEMICALS IN PRE-CLINICAL (ESCC) by suppressing the expression of nuclear transcription
TRIALS factor Nrf2 and Nrf2-driven antioxidant molecule NQO-1 and
HO-1, aggravating reactive oxygen species (ROS) generation,
In a bench to bedside drug development process, meticulous use DNA damage apoptosis, and cell cycle arrest (Zhang
of preclinical screening models can results into potential lead et al., 2017a).
compounds for anticancer drug development with extensive data Andrographolide is a bicyclic diterpenoid lactone isolated
on preliminary efficacy, toxicity, pharmacokinetic, and safety from Andrographis paniculata (Acanthaceae). Andrographolide
information which help to decide whether a molecule should be was found to inhibit tumor growth by blocking tumor adaptation
taken further for clinical trials. In the context of this review, to hypoxic condition (Li et al., 2015). The observed effect of
abundant evidence has been collected on preclinical efficacy of andrographolide (100 mg/kg) was due to inhibition of hypoxia-
number of phytochemicals (Figure 1) in various animal models inducible factor (HIF)-1a activity and its upstream PI3k/AKT/
which is summarized in Table 2. Brief information on each mTOR pathway (Li et al., 2015). More details on the therapeutic
phytochemical is as follows: potential of Andrographolide in cancer have been reviewed in
6-Shogaol is a minor, bioactive component isolated from Islam et al. (Islam et al., 2018).
ginger (Zingiber officinale, Roscoe). In a nude mice model of Apigenin (APG), is a naturally occurring flavonoid present in
non-small cell lung cancer (NSCLC), 6-shogaol (10 mg/kg) fruits and vegetables with diverse anticancer properties (reviewed
significantly inhibited the growth of NCI-H1650 lung cancer in Madunić et al., 2018). In athymic nude mouse xenograft with
cells which was associated with decreased cell proliferation and human chondrosarcoma Sw1353 cells, APG (5 mg/kg)
increased apoptosis as evidenced by reduced Ki-67-positive cells suppressed tumor growth which was associated with decrease
and an increased number of terminal deoxynucleotidyl in Ki67 expression and induction of apoptosis (Yan et al., 2018).
transferase deoxyuridine triphosphate nick-end labeling At molecular level APG regulated the expression of Bcl-2 family
(TUNEL)-positive cells. At in vitro level 6-shogaol suppressed protein and activated the caspase cascade to induce G2/M phase
Akt signaling through direct targeting of Akt1 and Akt2 (Kim arrest and apoptosis (Yan et al., 2018). In another study, APG
et al., 2014). In a syngeneic FVB/N mice model of prostate (3 mg/kg) targeted dipeptidyl peptidase IV (DPPIV) enzyme to
cancer, intraperitoneal administration of 6-shogaol (100 mg/kg reduce the growth and metastasis of NSCLC xenografts. In vitro
body weight) reduced tumor weight which was associated with mechanistic investigations showed that APG suppressed the
decrease in pSTAT3Y705 and both cyclin D1 and survivin levels snail/slug signaling and downregulated DPPIV enzyme to
(Saha et al., 2014). modulate the EMT and the invasive ability of both EGFR
Allicin, one of the main organic allyl sulfur components in positive and negative NSCLC cells (Chang et al., 2018). Some
garlic (Allium sativum, Amaryllidaceae), was examined for its of preclinical studies showed that the efficacy of APG enhanced
effects on cholangiocarcinoma (CCA) (Chen et al., 2018). In when combined with other chemotherapeutic agents (Hu et al.,
BALB/c nude mice model of CCA, allicin (10 mg/kg) 2018) or loaded in nanocarriers (Bhattacharya et al., 2018).
significantly suppressed the growth of human liver bile duct Baicalein and baicalin are the naturally occurring flavonoids
carcinoma (HuCCT-1). The in vitro molecular study showed and active components of Scutellaria baicalensis (Lamiaceae). In
that allicin (20 µM) reduced the levels of matrix NOD-scid IL2Rg null (NSG) mouse xenograft with human colon
metalloproteinase (MMP)-2 and -9, via reducing the activity of cancer HCT116 cells, baicalein (50 mg/kg) and baicalin (50 mg/
the STAT3 signaling pathway to decrease migration, invasion, kg) inhibited tumor growth and induced apoptosis (Dou et al.,
and epithelial-mesenchymal transition (EMT) of HuCCT-1 cell. 2018). At the in vivo level it down-regulated human telomerase
Additionally, allicin suppressed proliferation by activating the reverse transcriptase (hTERT) expression, and deactivated
caspase cascade, inducing apoptosis, and reducing the mitogen-activated protein kinase (MAPK), extracellular
expression of proteins downstream of STAT3, such as B-cell receptor kinase (ERK), and p38 signaling pathways (Dou et al.,

FIGURE 1 | Chemical structures of some anticancer phytochemicals in preclinical trials.
2018). In another study in nude mouse model of colon cancer, baicalein (50 mg/kg) additively inhibited the tumor growth by
intraperitoneal administration of baicalin (50 mg/kg) inhibited increasing apoptosis and decreasing tumor angiogenesis (Lu
tumor growth by repressing the expression of c-Myc and et al., 2018a).
oncomiRs microRNAs to induce apoptosis (Tao et al., 2018). Curcumin (phytopolylphenol) is a phytochemical from
Furthermore, in combination with docetaxel (10 mg/kg), Curcuma longa (Zingiberaceae). Several studies have reported

TABLE 2 | Phytochemicals in pre-clinical trials for cancer treatment.
Phytochemical Botanical name (family) Molecular targets Reference

(compound class)
6-Shogaol Zingiber officinale (Roscoe) Akt and STAT signaling pathway (Kim et al., 2014; Saha et al., 2014)
(phenylpropanoid)
Allicin (organosulfurs) Allium sativum STAT3 signaling pathway (Huang et al., 2017; Chen et al., 2018)
(Amaryllidaceae)
Alpinumisoflavone Derris eriocarpa Nrf2, NQO-1, HO-1, miR-101, and Akt signaling (Wang et al., 2017; Zhang et al., 2017a)
(pyranoisoflavone) (Leguminosae)
Andrographolide Andrographis paniculata HIF-1a, VEGF, and PI3K pathway (Li et al., 2015)
(diterpenoid) (Acanthaceae)
Apigenin (flavonoid) Petroselinum crispum Intrinsic apoptosis pathway (Chang et al., 2018; Yan et al., 2018)
(Apiaceae)
Baicalein (flavonoid) Scutellaria baicalensis MAPK, ERK, and p38 signaling pathways (Dou et al., 2018; Tao et al., 2018)
(Lamiaceae)
Baicalin (flavonoid) Scutellaria baicalensis MAPK, ERK, and p38 signaling pathways (Dou et al., 2018)
(Lamiaceae)
Curcumin Curcuma longa Modulates cell signaling and gene expression (Kunnumakkara et al., 2017)
(phytopolyphenol) (Zingiberaceae) regulatory pathways
Decursin and Decursinol Angelica gigas (Apiaceae) Not mentioned (Wu et al., 2017)
(Coumarin)
Dicumarol Melilotus officinalis Intrinsic apoptosis pathway (Zhang et al, 2017b)
(Fabaceae)
Epigallocatechin Camellia sinensis (Theaceae) Inhibit cell proliferation and apoptosis (Xu et al., 1992; Thangapazham et al., 2007)
(flavonoids)
Emodin (resin) Rheum palmatum L. PI3K/AKT and MAPK signaling pathways (Iwanowycz et al., 2016; Lin et al., 2016; Su et al.,
(Polygonaceae) 2017)
Genistein (isoflavonoid) Glycine max (legumes) WNT/b-catenin and Akt signaling pathway (Zhang et al., 2013; Hsiao et al., 2019)
Gingerol (polyphenol) Zingiber officinale (Roscoe) Intrinsic apoptosis pathway (Joo et al., 2016; Martin et al., 2017)
Glycyrrhizin (triterpenes) Glycyrrhiza glabra (Fabaceae) TxA2 and JAK/STAT signaling pathway (Deng et al., 2017)
Hispidulin (flavone) Salvia involucrate (Lamiaceae) Intrinsic apoptosis pathway (Gao et al., 2017; Han et al., 2018)
HS-1793 (stilbenoid) Polygonum cuspidatum HIF-1a, VEGF, Ki-67 and CD31 (Kim et al., 2017)
(Polygonaceae)
Licochalcone A (chalcone) Glycyrrhiza glabra (Fabaceae) Cyclins and CDKs (Lu et al., 2018b)
Nimbolide (triterpene) Azadirachta indica PI3K/AKT/mTOR and ERK signaling (Subramani et al., 2016)
(Meliaceae)
Physapubescin B (Steroid) Physalis pubescens L. Ki-67, Cdc25C, and PARP (Ding et al., 2015)
(Solanaceae)
Pterostilbene (polyphenol) Polygonum cuspidatum Mitochondrial mediated apoptosis; ERK and STAT3 (Feng et al., 2016; Kong et al., 2016; Wen et al.,
(Polygonaceae) signaling 2017)
Resveratrol (phenol) Polygonum cuspidatum Regulating cell cycle and apoptosis pathways (Banerjee et al., 2002)
(Polygonaceae)
Sulforaphane (organosulfur) Brassica oleracea Cell cycle arrest and apoptosis. Targets: caspase 8, (Qazi et al., 2010)
(Brassicaceae) p21, hsp90
Thymol (monoterpenoids) Thymus vulgaris (Lamiaceae) Mitochondrial mediated apoptosis (De La Chapa et al., 2018)
Thymoquinone (quinone) Nigella sativa STAT3 and associated protein (Zhu et al., 2016; Odeh et al., 2018)
(Ranunculaceae)
Ursolic acid (triterpenoids) Oldenlandia diffusa Ki-67, CD31, and miR-29a (Prasad et al., 2012; Zhang et al., 2018)
(Rubiaceae)
Withaferin-A (phytosterols) Withania somnifera AKT signaling FOX03a-Par-4 cell death pathway, ERK, (Choi and Kim, 2015; Suman et al., 2016;
(Solanaceae) and p38 pathway Kuppusamy et al., 2017)
anticancer potential of curcumin through modulation of extensively converted to decursinol in rodents and humans
multiple signaling and gene expression regulatory pathways (Zhang et al., 2015; Wu et al., 2017). In SCID-NSG mice
(Kunnumakkara et al., 2017). Curcumin inhibited the tumor xenograft with human prostate cancer LNCaP/AR-Luc cells
growth in mice subcutaneously injected with human A375 overexpressing the wild type androgen receptors (AR),
melanoma cells. Studies indicated that curcumin inhibited the decursinol (4.5 mg/mouse) decreases tumor growth and lung
growth of melanoma cells through mechanisms including cell metastasis (Wu et al., 2017).
cycle arrest, autophagy, and downregulation of the PI3K/AKT/ Dicumarol (DIC) is the natural anticoagulant derived from
mTOR/P70S6K pathway which is a critical intracellular signaling coumarin, by bacterial action in spoiled sweet clover hay
pathway associated with cell survival and death (Zhao (Melilotus officinalis, Fabaceae). In BALB/c nude mouse
et al., 2016). xenograft model, DIC (30 mg/kg) significantly suppressed the
Decursin and decursinol are coumarins purified from the growth of SKOV3 ovarian carcinoma cells (Zhang et al., 2017b).
dried roots of Angelica gigas Nakai. Decursin is rapidly and The in vitro molecular mechanistic studies suggested that DIC

inhibited the kinase activity of pyruvate dehydrogenase kinase 1 Gingerol is a major phenolic compound present in the
(PDK1), shifted the glucose metabolism from aerobic glycolysis rhizomes of ginger (Z. officinale Roscoe). In a syngenic mouse
to oxidative phosphorylation, generated a higher level of ROS, model of spontaneous breast cancer metastasis, gingerol (5 mg/
attenuated the mitochondrial membrane potential (MMP), kg) treatment induced caspase-3 activation and inhibited the
induced apoptosis, and reduced cell viability of SKOV3 cells. orthotopic tumor growth as well as metastasis of mouse brain-
Notably, DIC (32 mg/kg) was found safe toward ovarian tissues metastatic 4T1Br4 mammary tumor cells to multiple organs such
and developing oocytes; implicating importance of DIC as a as lung, bone and brain (Martin et al., 2017). Likewise, Joo and
potential anticancer agent when female fertility preservation is a colleagues (Joo et al., 2016) reported inhibition of lung-
concern (Aras et al., 2016). metastatic, MDA-MB-231 human breast cancer cell
Epigallocatechin (EGCG), a major catechin found in green proliferation, and invasion by [10]-gingerol through
tea, effectively delayed the tumor incidence and reduced tumor suppression of Akt, p38MAPK, and epidermal growth factor
burden by inducing apoptosis and inhibiting proliferation of receptor. The detailed protective and therapeutic potential of
human breast cancer MDA-MB-231 cells in nude mouse model gingerol in cancer is reviewed in de Lima et al. (2018).
(Thangapazham et al., 2007). In another study, EGCG Glycyrrhizin (GA) is the major bioactive component found in
suppressed the increase of oxidative stress-derived DNA licorice roots of a small leguminous shrub, Glycyrrhiza glabra L.
damage marker 8-hydroxydeoxyguanosine (8-OH-dGuo) levels In athymic BALB/c nude mice xenograft with human lung
in mouse lung DNA to inhibit nitrosamine (NNK)-induced lung adenocarcinoma A549 cells stably transfected with TxA2
tumorigenesis (Xu et al., 1992). receptor (TPa), GA (135 mg/kg) reduced thromboxane
Emodin is an anthraquinone derivative from the root and synthase (TxAS) and proliferating cell nuclear antigen (PCNA)
rhizome of Rheum palmatum L. (Polygonaceae). In a BALB/c expression via suppressing TxA2 pathway (Deng et al., 2017).
nude mice, emodin (50 mg/kg) inhibited the growth of human More recent findings showed that GA (100 mg/kg) inhibited the
lung epithelial (A549) cells by inducing endoplasmic reticulum growth of non-small cell lung cancer cells (NSCLC) in patient-
(ER) stress-dependent apoptosis. The in vitro molecular derived xenograft (PDX) mice by suppressing the level of high
mechanism showed that emodin activated ER stress and mobility group box 1 (HMGB1) and inhibition of JAK/STAT
TRIB3/nuclear factor-kB signaling (Su et al., 2017). In mice signaling pathway (Wu et al., 2018b).
bearing EO771 or 4T1 breast tumors, emodin suppressed tumor Hispidulin is a phenolic flavonoid compound found in
growth by inhibiting macrophage infiltration and M2-like different plant materials such as Saussurea involucrata Kar
polarization, accompanied by increased T-cell activation and (Asteraceae). Intraperitoneal administration of hispidulin (20
reduced tumor angiogenesis (Iwanowycz et al., 2016). At mg/kg) inhibited the Caki-2 (human clear cell renal cell
molecular level, emodin inhibited IRF4, STAT6, and C/EBPb carcinoma) tumor growth and lung metastasis in athymic
signaling and significantly increased inhibitory histone H3 lysine BALB/c nu/nu mouse model by increasing the expression of
27 tri-methylation (H3K27m3) on the promoters of M2-related cleaved caspase-3 and decreasing the activity of Sphk1, thereby
genes in tumor-associated macrophages (Iwanowycz et al., 2016). modulating ceramide-S1P balance (Gao et al., 2017). Similarly, in
In BALB/c nude mice xenograft with human hepatocellular another study, hispidulin (20 mg/kg) effectively suppressed
cancer SMMC-7721 cells, emodin suppressed tumor growth human hepatocellular carcinoma Bel7402 cell xenograft tumor
and induced apoptosis with increases in ERK and p38 growth and lung metastasis in by increasing the expression of
phosphorylation and suppression of p-JNK expression (Lin PPARg and phosphorylation levels of AMPK, JNK and ERK
et al., 2016). proteins (Han et al., 2018).
Genistein is a naturally occurring isoflavone present in soy HS-1793 is a synthetic analogue of resveratrol with improved
beans with estrogen-like properties. Genistein (140 mg/kg) photosensitivity and stability profile. In a nude mouse model of
treatment decreased the number of total aberrant crypts in the breast cancer, HS-1793 (5 mg/kg) significantly suppressed the
azoxymethane (AOM)-induced rat colon cancer model through growth of human breast cancer MDA-MB-231 cells with
the inhibition of aberrant nuclear accumulation of b-catenin and decreased expression of Ki-67 and CD31 proteins. Moreover, HS-
suppression of WNT signaling genes (Zhang et al., 2013). In 1793 treatment downregulated expression of HIF-1 and vascular
athymic BALB/c nu/nu mouse xenograft with human leukemia endothelial growth factor (VEGF) protein both of which are key
cell line HL‐60, intraperitoneal injected of genistein (0.4 mg/kg) components of the angiogenic process (Kim et al., 2017). Apart from
for 28 days significantly reduced the tumor weight without its growth inhibitory and antiangiogenesis effects, HS-1793
affecting the body weight (Hsiao et al., 2019). At in vitro level, enhanced ionizing radiation-induced apoptosis and inhibited
genistein‐induced G2/M phase arrest and apoptosis of HL‐60 hypoxia-induced cancer stem cell properties in hypoxic mouse
cells through ROS mediated ER stress leading to increased Ca2+ breast cancer FM3A cells (Choi et al., 2016).
production and decreased mitochondrial membrane potential. Licochalcone A (LicA) is a phenol chalconoid isolated from
At molecular level, the observed effect was due to increased the roots of Glycyrrhiza species. In athymic BALB/c nu/nu
expression of ER stress-associated proteins (IRE‐1a, calpain 1, mouse model, LicA (20 mg/kg) inhibited the human cervical
GRP78, GADD153, caspase‐7, caspase‐4, and ATF‐6a) and cancer cell SiHa tumor growth via inhibition of the PI3K/Akt/
apoptosis associated proteins (Bax, PARP‐cleavage, caspase‐9, mTOR signaling pathway and induction of apoptosis (Tsai et al.,
caspase‐3, Bcl‐2, and Bid) (Hsiao et al., 2019). 2015). In athymic nude mice subcutaneous or orthotopic

xenograft with human glioma U87 cells, LicA induced cell cycle resveratrol reduced the incidence and multiplicity of tumors,
arrest in the G0/G1 and G2/M phases by reducing the expression concurrently extending the latency period. In the same study,
of cyclins and cyclin-dependent kinases (Lu et al., 2018b). Most resveratrol could suppress activation of nuclear factor-kB which
recently, LicA was shown to suppress hexokinase 2-mediated regulates the gene expression of cyclooxygenase-2 and matrix
tumor glycolysis in gastric cancer via downregulation of the Akt metalloproteinase-9 (Banerjee et al., 2002).
signaling pathway (Wu et al., 2018a). Sulforaphane (SFN) is a compound within the isothiocyanate
Nimbolide is a triterpene derived from the leaves and flowers group of organosulfur compounds. SFN exerts its anticancer
of the neem tree (Azadirachta indica). In an athymic nu/nu effects by modulating key signaling pathways such as induction
mouse model, nimbolide (5 mg/kg) inhibited the pancreatic of apoptosis, inhibition of cell cycle progression, inhibition of
cancer HPAC cell growth and metastasis by inducing apoptosis angiogenesis, and by increasing anticancer activity of other
(Subramani et al., 2016). The in vitro molecular mechanism antiproliferative agents including paclitexal (Qazi et al., 2010;
studies showed that nimbolide increased ROS generation, (Su et al., 2018). Addition of SFN and paclitexal to Barrett
inhibited proliferation (through reduced PI3K/AKT/mTOR esophageal adenocarcinoma (BEAC) cells significantly
and ERK signaling) and metastasis (through decreased EMT, increased apoptotic cell death compared to SFN or paclitexal
invasion, migration, and colony forming abilities) via (Qazi et al., 2010). A significant reduction in tumor volume was
mitochondrial-mediated apoptotic cell death. Recent in vitro also observed by SFN in severe combined immunodeficient
study suggested epigenetic role of nimbolide in regulating (SCID) mice subcutaneously injected with BEAC cells (Qazi
autophagy and apoptosis in human breast cancer cells et al., 2010).
(Pooladanda et al., 2018). Thymol is a transient receptor potential ankyrin subtype 1
Physapubescin B is a steroidal substance isolated from (TRPA1) channel, agonist found in thyme (Thymus vulgaris) and
Physalis pubescens L. (Solanaceae). In nude mouse models with oregano (Origanum vulgare). In oral squamous cell carcinoma
prostate cancer xenografts, physapubescin B (50 mg/kg) Cal27‐ and HeLa‐derived mouse xenografts, intratumor
decreased PC3 tumor growth by reducing the expression levels injection of thymol (4.3 mmol/L) reduced the tumor volume
of Ki-67, Cdc25C, and full length PARP and increasing the with decreasing cell proliferation and inducing apoptosis as
apoptotic cell population within the tumor tissue (Ding et al., observed by Ki-67 staining and TUNEL assays, respectively
2015). Furthermore, in renal cell carcinoma 786-O cells, (De La Chapa et al., 2018). The in vitro molecular mechanism
physapubescin (30 mg/kg) decreased the protein expression of studies showed that thymol induced depolarization of
vimentin and inhibited in vivo angiogenesis (Chen et al., 2016). mitochondrial membrane potential to induce apoptosis (De La
Pterostilbene is a naturally occurring derivative of resveratrol Chapa et al., 2018).
originated from grape (Vitis vinifera, Vitaceae). In an athymic Thymoquinone (2-isopropyl-5-methyl-1,4-benzo-quinone,
nude mouse esophageal cancer model, pterostibene (100 or 200 TQ) is the active constituent of black cumin (Nigella sativa,
mg/kg) significantly inhibited EC109 tumor growth, cell Ranunculaceae) seed oil. In a BALB/c athymic nude mice, TQ
adhesion, migration, and intracellular glutathione (GSH) levels (10 mg/kg) decreased tumor weight and size by inducing
while increasing the apoptotic index, caspase 3 activity, and ROS apoptosis and inhibiting STAT3 phosphorylation in human
levels (Feng et al., 2016). Similarly, in a athymic nude mouse gastric cancer cells. The downregulation of STAT3 activation
model of diffuse large B-cell lymphoma, pterostibene (30 mg/kg) was associated with a reduction in JAK2 and c-Src activity (Zhu
markedly inhibited tumor growth, reduced MMP, increased et al., 2016). Recent preclinical studies suggested the potential of
cellular apoptotic index and ROS levels, leading to S-phase TQ in adjuvant therapy with other chemotherapeutic agents
arrest in the cell cycle (Kong et al., 2016). More importantly, it (reviewed in Mostofa et al., 2017). In another study in BALB/c
was demonstrated that pterostilbene (30 mg/kg) with megestrol mice transplanted with mouse epithelia breast cancer EMT6/P
acetate (10 mg/kg) significantly reduced HEC-1A tumor growth cell line, TQ in combination with melatonin significantly
in an endometrial cancer xenograft mouse model as compared to decreased the tumor size, induced tumor cell death, decreased
pterostilbene or megestrol acetate alone (Wen et al., 2017). At in VEGF expression, and activated anticancer immune response by
vitro level, the above combination suppressed ERK and STAT3 increasing serum interferon (INF)-g level (Odeh et al., 2018).
signaling pathways and estrogen receptor expression. Ursolic acid (UA) is a natural terpene compound found in a
Resveratrol is a polyphenolic phytoalexin (stilbenoid). variety of natural plants. Anticancer activity of UA is well known
Numerous reports have shown that resveratrol suppresses with recent studies suggesting the use of UA as a cancer
proliferation of a wide variety of tumor cells, including breast, chemosensitizer to standard chemotherapeutic drugs (Prasad
colon, prostate, liver, and lung (Banerjee et al., 2002). Resveratrol et al., 2016). In one study UA was shown to enhance the
significantly reduced tumor growth and metastasis to the lung in therapeutic effects of oxaliplatin in mouse model of CRC by
mice bearing highly metastatic Lewis lung carcinoma tumors inhibiting the tumor and increasing the survival rate. The in vitro
(Kimura and Okuda, 2001). The results suggested that the mechanistic study suggested that treatment of CRC cells with UA
antitumor and antimetastatic activities of resveratrol could and oxaliplatin significantly inhibited cell proliferation, increased
result from the inhibition of DNA synthesis, inhibition of apoptosis and ROS production, and significantly inhibited
neovascularization, and angiogenesis. In 7,12-dimethylbenz(a)- expression of drug resistant gene (Zhang et al., 2018). The UA
anthracene (DMBA)-induced mammary cancer model, nanoparticles decreased tumor size by targeting caspases and p53

with downregulation of Bcl-2 and cIAP, inducing apoptosis and randomized, double-blind and placebo-controlled phase 3
leading to cervical cancer cell death (Wang et al., 2018). clinical trial, administration of berberine (1 g/day) was found
Withaferin A (WA) is a steroidal lactone present in Withania to be safe in type 2 diabetic patients with dyslipidemia (Zhang
somnifera (Solanaceae). In a nude mouse model of colorectal et al., 2008). Currently, a randomized, double-blind, placebo-
cells (CRC), oral administration of WA (5 mg/kg) inhibited the controlled phase 2/3 trial is ongoing to determine the efficacy of
tumor growth of human colorectal carcinoma (HCT-116) cells berberine hydrochloride (300 mg/twice/day) against the
overexpressing AKT and micro-vessel formation. At in vitro level occurrence of new colorectal adenomas among 1,000 patients
in AKT overexpressing HCT-116 cells, WA inhibited cell with a history of colorectal cancer (NCT03281096).
proliferation, migration, and invasion by downregulating EMT Curcumin, a yellow polyphenolic pigment, is an active
markers (snail, slug, b-catenin, and vimentin) (Suman et al., ingredient in turmeric (Curcuma longa; Zingiberaceae) and is a
2016). In another study, intraperitoneal administration of highly promising chemopreventive agent. Several groups
withaferin-A (2 mg/kg) inhibited CRC growth by blocking reported the chemopreventive and chemotherapeutic role of
interleukin-6-induced activation of STAT3 (Choi and Kim, curcumin in different cancer cells including blood (Taverna
2015). Similarly, in another study, oral administration of WA et al., 2015), breast (Mock et al., 2015), head and neck
(4 mg/kg) effectively inhibited HepG2-xenografts and (Wilken et al., 2011), liver (Darvesh et al., 2012), prostate
diethylnitrosamine (DEN)-induced-hepatocellular carcinoma (Nakamura et al., 2002), ovary (Yallapu et al., 2010), and skin
(HCC) in C57BL/6 mice by elevating the levels of ERK, RSK, cancers (Huang et al., 1997). This has warranted studies in
ELK1, and DR5 along with decreased expression of Ki67. The in clinical trials to address pharmacokinetics, safety, and efficacy
vitro molecular mechanism studies suggested WA increased issues of curcumin in humans. Phase I clinical trials have shown
phosphorylation of ERK and p38 leading to increased safety, tolerability, and nontoxicity of curcumin even at high
phosphorylation of p90-ribosomal S6 kinase (RSK) and a doses (8 g/day) but exhibited poor bioavailability in humans
concomitant activation of ETS-like transcription factor-1 (Sharma et al., 2004; Kanai et al., 2013). Despite bioavailability
(ELK1) and death receptor protein-5 (DR5) (Kuppusamy challenges, clinical trials with curcumin either alone or in
et al., 2017). combination as an anticancer agent have shown efficacy
against several disease sites such as breast (Bayet-Robert et al.,
2010), prostate (Mahammedi et al., 2016), pancreatic (Epelbaum
PHYTOCHEMICALS EVALUATED IN et al., 2010; Kanai et al., 2013), colorectal (Sharma et al., 2004;
CLINICAL TRIALS Carroll et al., 2011; Irving et al., 2015; James et al., 2015), and
hematological malignancies (Ghalaut et al., 2012). Latest
Clinical trials using phytochemicals against cancer are still in information on various preclinical and clinical anticancer trials
infancy through an overwhelming large number of anti-cancer using curcumin is reviewed in Doello et al. (2018). Recently, in
compounds are currently under development. The clinical trials patients with locally advanced or metastatic pancreatic cancer,
with phytochemicals focus on three major aspects of cancer curcumin Meriva ® (2,000 mg/day) in complementary to
research: 1) improving the response of cancer cells toward gemcitabine was found to increase the efficacy of gemcitabine
standard chemo- and radiotherapy, 2) reducing the severe without any treatment-related toxicity (Pastorelli et al., 2018).
adverse effects of standard cancer therapy, and 3) looking for Currently, a randomized, double-blind, placebo-controlled phase
unwanted interactions with standard therapy. Preclinical studies 2/3 trial is ongoing to determine the efficacy of curcumin (300
have shown the effectiveness of various phytochemicals such as mg/i.v./day) along with Paclitaxel (80 mg/m2 BS; i.v.)
berberine, curcumin, green tea, catechins including EGCG, administrated once weekly for 12 weeks against the advanced
lycopene, quercetin, resveratrol, and sulforaphane (Figure 2). and metastatic breast cancer patients (NCT03072992). Apart
The phytochemicals which are currently under clinical trials from this study, 18 other actively ongoing oncology-based trials
against various cancers are summarized in Table 3 and their brief using curcumin are registered on clinicaltrials.gov.
description is given below: Epigallocatechin (EGCG) is a major catechin found in
Berberine, a benzyl-tetra isoquinoline alkaloid found in green tea (Camellia sinensis; Theaceae). Numerous studies
Berberis sp. (Berberidaceae) has long been a part of traditional using cell lines and animal models have established anticancer
Chinese and Ayurvedic medicine. Preclinical efficacy of activity of EGCG (Wang and Bachrach, 2002; Fujiki et al.,
berberine has been established in various cancers including 2015). Data from clinical trials provide evidence of safety of
colon (Mao et al., 2018), breast (Zhao et al., 2017), catechin mixture containing EGCG (200 mg/day) in men
gastrointestinal (Hesari et al., 2018), oral (Lin et al., 2017), diagnosed with high-grade prostatic intraepithelial neoplasia
liver (Tsang et al., 2015), pancreas (Abrams et al., 2019), (HGPIN) and/or atypical small acinar proliferation (ASAP)
prostate (Youn et al., 2018), ovarian (Hou et al., 2017), and (Kumar et al., 2016). In a randomized, presurgical placebo-
cervical (Mahata et al., 2011) cancers. Despite large preclinical controlled phase II pilot study of polyphenon E (a green tea
efficacy data, clinical trials related to the evaluation of true polyphenol formulation primarily consisting of EGCG; 1,200
potential of berberine as an anticancer agent are limited. Most mg/day) in bladder cancer patients, EGCG accumulated in
of the clinical trials have demonstrated the safety of berberine cancer tissue and decreased the level of proliferation (PCNA)
against other clinical conditions such as type 2 diabetes. In a and apoptosis (clusterin) biomarkers (Gee et al., 2017).

FIGURE 2 | Chemical structures of some anticancer agents in clinical trials.
Moreover, recent study has suggested the use of EGCG in (Gontero et al., 2015). Interestingly, in a recent metabolomic
combination with indole-3-carbinol for better treatment study on men with increased PSA levels but no prostate cancer,
outcomes in advanced ovarian cancer patients (Kiselev et al., intake of lycopene (15 mg) along with GTCs (EGCG 600 mg) for
2018). Currently, a randomized, early phase 1 trial is ongoing 6-months reduced the levels of circulating pyruvate. The study
to evaluate the chemopreventive effects of Teavigo™ (highly using Mendelian randomization analysis suggested association
purified and refined green tea extract providing 94% EGCG) of pyruvate level with prostate cancer risk (Beynon et al., 2019).
(450 mg/PO/day) in colorectal cancer (CRC) patients with Overall, with the scarcity and heterogeneity of existing clinical
curative resections (NCT03072992). evidences, the conclusions drawn can be conflicting or
Lycopene, a naturally occurring chemical that gives fruits and ambiguous. Nevertheless, currently double-blind, placebo-
vegetables a red color, is abundantly found in red tomatoes controlled phase 2 trial is ongoing to assess the effectiveness of
(Solanum lycopersicum; Solanaceae). In the meta-analysis of lycopene (20 mg/PO/day) to reduce skin toxicity in
Chen et al. (6 cohort and 11 nested case-control studies), the metastasis colorectal carcinoma patients treated with
intake of lycopene/tomato was associated with relatively minor panitumumab (NCT03167268).
reduction in the risk of prostate cancer diagnosis in men Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a
consuming a higher level of lycopene (Chen et al., 2013). In a stilbenoid, which is found largely in the skins of red grapes
randomized, double blinded, controlled trial in patients with (Polygonum cuspidatum; Polygonaceae). In a phase I study on
multifocal high grade prostatic intraepithelial neoplasia men with elevated PSA level in recurrent prostate cancer,
(HGPIN) and/or atypical small acinar proliferation (ASAP), pulverized muscadine grape skin extract (MPX) containing
administration of high dose supplement containing lycopene 4,000 mg resveratrol, compared with placebo, delayed the
(35 mg), selenium (55 µg), and 600 mg green tea catechins development of recurrence by lengthening the prostate
(GTCs) for 6 months, insignificantly decreased the prostate specific antigen doubling time (PSADT) by 5.3 months
specific antigen (PSA) levels, but increased incidence of (Paller et al., 2015). Moreover, 12-month treatment with
prostate cancer at re-biopsy and expression of microRNAs MPX did not significantly prolong PSADT over two
associated with prostate cancer progression (Gontero et al., different doses, low (500 mg) or high (4,000 mg) (Paller
2015). The study suggested avoiding the use of high doses of et al., 2018). In a pilot study on patients with colorectal
supplements in patients with prostatic intraepithelial neoplasia cancer with hepatic metastases, resveratrol (5.0 g/day for 14

TABLE 3 | List of phytochemicals currently in clinical trial on various cancers.
Phytochemical Class of com- Type of cancer Assessment Reference

pound
Berberine Berberis sp. Colorectal cancer Prevention of recurrence NCT03281096*

(alkaloid) (Berberidaceae)
Curcumin Curcuma longa Advanced and metastatic Quality of life, safety in combination, progression free survival, time to disease NCT03072992*
(polylphenol) (Zingiberaceae) breast cancer Progression, and time to treatment failure
Epigallocatechin Camellia sinensis Colorectal cancer Change in methylation pattern compare to baseline NCT02891538*
(flavonoids) (Theaceae)
Lycopene Solanum Metastatic colorectal Effectiveness in reducing skin toxicity alone or in combination with panitumumab. NCT03167268*
(carotenoids) lycopersicum cancer Pharmacokinetics.
(Solanaceae)
Quercetin Prostate cancer EGCG, ECG, quercetin, and their methylated metabolites in prostate tissue and NCT01912820*
(carotenoids) plasma. Enzyme activity expression of COMT, DNMT1, and MRP1. Inter-individual
variation in genotype of COMT
Resveratrol Polygonum Low-grade GI Notch1 activation, toxicity NCT01476592*
(stilbenoid) cuspidatum neuroendocrine tumors
(Polygonaceae)
Sulforaphane Brassica Former smokers with a Bronchial dysplasia index, cell proliferation marker Ki-67, apoptosis markers NCT03232138*
(isothiocyanate) oleracea high risk of developing including caspase-3 and TUNEL
(Brassicaceae) lung cancer
*Indicates reference found at www.clinicaltrials.gov with corresponding identifier code (NCT).
days) was detected in hepatic tissue where cleaved caspase 3, a chemopreventive effect of Avmacol (sulforaphane) tablets (120
marker of apoptosis, was significantly increased in malignant µM/p.o./twice/day) in former smokers with a high risk of
hepatic tissue (Howells et al., 2011). In another pilot study on developing lung cancer (NCT03232138).
39 women at increased risk for breast cancer, trans-resveratrol
(50 mg twice a day for 12 weeks) decreased methylation of Ras
association domain family 1 isoform A (RASSF)-1a, a gene
associated with breast cancer, increased levels of trans- PHYTOCHEMICALS USED IN CURRENT
resveratrol and resveratrol-glucuronide in the circulation, CANCER THERAPY
and decreased cancer promoting PGE2 expression in the
breast (Zhu et al., 2012). Recently, a clinical trial aimed at The four major classes of clinically used plant-derived anticancer
studying the effect of resveratrol (2.5 gm/p.o./twice/day) on compounds include vinca alkaloids, taxane diterpenoids,
Notch-1 signaling in low-grade gastrointestinal camptothecin derivatives, and epipodophyllotoxin (Figure 3
neuroendocrine tumors was completed (NCT01476592). and Table 4). Apart from these phytochemical classes, other
However No study results are posted so far on this plant-derived anticancer agents from different classes such as
clinical trial. combretastatins, homoharringtonine (omacetaxine
Sulforaphane (SFN) is a dietary isothiocyanate found in mepesuccinate, cephalotaxine alkaloid), and ingenol mebutate
cruciferous plants such as broccoli (Brassica oleracea, are also used (Figure 3 and Table 4). Poor aqueous solubility and
Brassicaceae). Cipolla et al. conducted a double-blinded, significant toxic side effects still remain the major concern and
randomized, placebo-controlled trial with SFN in 78 patients therefore, the current focus of research is toward eradicating the
with increased PSA levels after radical prostatectomy. Oral impact of these factors. In this context, several analogues and
administration of sulforaphane (60 mg/day) for 6 months prodrugs have been synthesized and methods have been devised
significantly increased PSA doubling time (PSADT) and did to enhance aqueous solubility and tumor specificity. Brief
not show any adverse events as compared to the placebo group. description of a few phytochemicals which are used in cancer
Moreover, PSA slopes which were measured 2 months after SFN therapy is given below:
treatment remained the same (Cipolla et al., 2015). In a single
arm trial, Alumkal et al. carried out the efficacy, safety, Vinca Alkaloids
pharmacokinetics, and pharmacodynamics study of SFN-rich Vinca alkaloids are a subset of drugs obtained from the pink
broccoli sprout extracts (200 mmoles/day) administrated for 20 periwinkle plant Catharanthus roseus (Apocynaceae). The
weeks in patients (20) with biochemical (PSA) recurrent prostate Vinca alkaloids achieve cytotoxic effects by binding to b-
cancer. Even though, the primary endpoint was not achieved, tubulin at a site distinct from that of the taxanes thereby
there was a significant increase in on-treatment PSADT as inhibiting polymerization and assembly of microtubules,
compared to pre-treatment PSADT (6.1 months pre-treatment leading to metaphase arrest and cell death. As the
vs. 9.6 months) (Alumkal et al., 2015). Currently, double-blind, microtubules are associated with several other cellular
placebo-controlled phase 2 trial is ongoing to assess the functions such as maintenance of cell shape, motility, and

FIGURE 3 | Chemical structures of some anticancer agents in clinical use.
transport between organelles, the vinca alkaloids affect both for almost 50 years. A series of semisynthetic analogues of
malignant and non-malignant cells in the non-mitotic cell these two alkaloids have been developed (Table 4).
cycle. Vinblastine and vincristine are the two naturally V i n o r e l b i n e a n d v i n d e s i n e a r e t h e t w o e ff e c t i v e
isolated alkaloids that have been used in clinical oncology semisynthetic analogues that are approved for clinical use.

TABLE 4 | Compounds used for cancer treatment.
Class of phyto- Pharmacological action Type of cancer Molecular

chemical targets
Vinca alkaloids
Vinblastine Inhibit microtubule polymerization and Non-small-cell lung carcinoma (NSCLC), breast, lung, leukemia, Tubulin (Martino
Vincristine assembly, leading to metaphase arrest and Hodgkin and non-Hodgkin lymphomas, testicular carcinoma, et al., 2018)
Vindesine cell death. Kaposi’s sarcoma, and second-line transitional cell carcinoma of
Vinflunine the urothelium (TCCU)
Vinorelbine
Taxanes
Cabazitaxel Inhibit microtubule function resulting in cell NSCLC, head and neck, breast, prostate, gastric adenocarcinoma Tubulin (Kotsakis
Docetaxel cycle arrest and aberrant mitosis et al., 2016;
Paclitaxel Oudard
et al., 2017)
Podophyllotoxin
Etoposide Inhibits DNA synthesis by forming a complex Osteosarcoma, NSCLC cervical, nasopharyngeal, colon, breast, Topoisomerase (Cao et al.,
Teniposide with topoisomerase II and DNA. prostate, and testicular cancer II 2015)
Camptothecin
Irinotecan Stabilizes topoisomerase I-DNA complex Ovarian, cervical, colorectal, and small cell lung cancer (SCLC) Topoisomerase (Hertzberg
Topotecan thereby preventing religation of single strand I et al., 1989)
breaks resulting in lethal double-stranded
breaks in DNA.
Other plant-derived anticancer agents
Combretastatin A4 Inhibits polymerization of tubulin causing Polypoidal choroidal vasculopathy, anaplastic thyroid cancers Tubulin (Tozer et al.,
disruption of the tumor endothelial cells lining 2002)
the tumor vasculature
Homoharringtonine Binds to large ribosomal subunit, which Chronic myeloid leukemia Ribosomoal (Itokawa
affects chain elongation and prevents protein protein et al., 2005)
synthesis
Ingenol mebutate Rapid induction of cell death and activation Actinic keratosis Protein kinase (Skroza
of inflammatory response C et al., 2018)
These agents have been generally included in combination penetrate the blood–brain barrier in vivo, which is not
chemotherapy for the treatment of a variety of cancers, achievable with other taxanes. Some of the paclitaxel
including leukemia, Hodgkin and non-Hodgkin lymphomas, analogues such as larotaxel, milataxel, ortataxel, and
advanced testicular carcinoma, breast and lung cancers, and tesetaxel are currently undergoing clinical evaluation.
Kaposi’s sarcoma. Recently, vinflunine, a second-generation
gem-difluoromethylenated derivative of vinorelbine, has been Camptothecins
approved for the treatment of second-line transitional cell Camptothecin is a quinolone alkaloid isolated from the
carcinoma of the urothelium (TCCU). A comprehensive Chinese tree Camptotheca acuminata. Camptothecin
discussion of these agents is presented in the review by complexes with type I DNA topoisomerase preventing both
(Martino et al., 2018). cleavage and religation of DNA leading to a DNA double-
strand break and cytotoxicity (Hertzberg et al., 1989). At
Taxanes present, irinotecan and topotecan are the two FDA approved
Taxanes represent promising anticancer drugs that were first semi-synthetic camptothecin derivatives that are clinically
isolated from the bark of the Yew tree. Taxanes exert an active and less toxic than the parent compound. Irinotecan is
anticancer affect by stabilization of microtubules, resulting in prescribed for treatment of advanced cancers of the large
cell cycle arrest and aberrant mitosis. Paclitaxel, a natural intestine and rectum. Whereas, topotecan is approved for the
product isolated from the bark and leaf of Taxus brevifolia and treatment of recurring ovarian, small cell lung cancer, and
docetaxel, a semi synthetic derivative, is primarily used in cervical cancer.
breast, ovarian, pancreas, prostate, and lung cancer therapies.
A number of semisynthetic derivatives have been developed Podophyllotoxins
with improved cytotoxicity in resistant tumors, decreased Podophyllotoxin is a natural product isolated from Podophyllum
toxicity, and improved solubility. For example, cabazitaxel a p e l t a t u m a n d P o d o p h y l l u m e m o d i ( B e r b e r i da c e a e ) .
second-generation docetaxel derivative exhibits cytotoxic Podophyllotoxin reversibly binds to tubulin, whereas its key
activity against various docetaxel-resistant tumors with less derivatives etoposide and teniposide inhibit topoisomerase II,
overall toxicity (Kotsakis et al., 2016; Oudard et al., 2017). An inducing topoisomerase II-mediated DNA cleavage. Moreover,
additional characteristic of cabazitaxel is its ability to podophyllotoxin also exhibits potential anti-multidrug resistant

(MDR) activity against diverse drug-resistant tumor cells. For ethnopharmacological information providing ideal
example, CIP-36, a podophyllotoxin derivative, has been shown opportunities to limit the huge diversity of possible leads to
to overcome the MDR of adriamycin-resistant human leukemic more promising ones. A novel approach of integrated drug
cell line K562/ADR by regulating the activity of topoisomerase- discovery where ethnopharmacological knowledge is
IIa (Cao et al., 2015). However, CIP-36 failed in clinical trials due supported by broad interdisciplinary forces involving
to lack of efficacy and unacceptable toxicity. medicinal chemistry, pharmacology, biochemistry,
molecular, and cellular biology along with natural product
Other Plant-Derived Anticancer Agents chemistry is necessary to harvest the full potential of
Ingenol mebutate (IM) is a hydrophobic ester of the diterpene phytochemicals. Additionally, the advances in analytical
ingenol isolated from common Australian plant Euphorbia technology and computational methodologies, as well as the
peplus (Euphorbiaceae). IM is approved for the topical development of self-teaching artificial intelligence systems will
treatment of actinic keratosis, a common skin condition that facilitate the identification of new phytochemical lead entities
results from exposure to chronic ultraviolet radiation which can for pharmacological evaluation.
lead to squamous cell carcinoma, if not treated. IM presents two In the present review, the results observed in different
mechanisms of action: at high concentrations (~200–300 µM), it phases of clinical trials along with exciting preclinical results
induces rapid induction of cell death in the treated area and at indicate that the ways and means to take phytochemicals “from
low concentrations (~0.1 µM) it activates inflammatory bench to real-life situations” are on the horizon. In spite of the
response, capable of eliminating the residual cells. promise shown by phytochemicals as therapeutic agents in
Pharmacology, mode of action, pharmacokinetics, dosing, and cancer, there are some limitations which need to be resolved.
rout of administration of ingenol mebutate have been reviewed For instance, most of the phytochemicals studied at the
in more details by Skroza et al. (2018). preclinical stage lack insight into the molecular interaction
Homoharringtonine (HHT) is a naturally-occurring ester of with different signaling molecules. To address issues related to
the alkaloid cephalotaxine isolated from various trees of the molecular targets and pathways, in silico strategies like
Cephalotaxus genus (Cephalotaxaceae) and is approved for the molecular docking need to be employed to understand the
treatment of chronic myeloid leukemia. HHT binds to the A-site interaction of phytochemicals in different signaling pathways
cleft in the large ribosomal subunit, which affects chain that can be further validated by various in vitro and in
elongation and prevents protein synthesis. The discovery and vivo models.
development of HHT and related compounds is In most of the related clinical studies, the presence of
comprehensively reviewed by Itokawa et al. (Itokawa et al., methodological flaws including lack of control or placebo
2005). A semi-synthetic version of HHT, also known as group, small sample sizes, and short duration of the trial are
omacetaxine mepesuccinate, has been reported to be an observed. Therefore, for many phytochemicals, it is too early to
effective treatment for myelodysplastic syndromes (MDS) and conclude their anticancer actions and hence large-scale and
chronic myelomonocytic leukemia (CMML) in patients with well-controlled clinical trials are needed to validate their
resistance and intolerance toward hypomethylating agents such efficacies, adverse effects, and safeties before their use for the
as azacitidine and decitabine (Short et al., 2019). treatment of cancer. Moreover, extensive standardization in
The combretastatins are a family of several cis-stilbenes terms of methods for evaluating their bioavailability, efficacy,
from Cape bushwillow (Combretum caffrum, Combretaceae), a safety, quality, composition, manufacturing processes,
shrub from South Africa. Compounds in the combretastatin regulatory and approval practices, need to be carried out on
class indirectly act on cancer cells by inhibiting tubulin the promising phytochemicals to meet the international
polymerization causing disruption of the tumor endothelial standard. Paradoxically, vast knowledge and experience in
cells lining the tumor vasculature, inducing rapid vascular drug development are available in the pharmaceutical
collapse in solid tumors (Tozer et al., 2002). Combretastatin industry. Therefore, combining the benefits provided by both
A1 and combretastatin A4 are the two naturally isolated traditional and modern medicine has been previously
compounds. Combretastatin A4 phosphate (CA4P) is a suggested as a promising approach to reveal and to bring
phosphate prodrug of combretastatin A4 which has been new plant-derived substances to market. Synergistic or
designated as an orphan drug by the US Food and Drug additional effects of combinations of chemotherapeutic
Administration (FDA) and is approved for the treatment of a agents and phytochemical compounds in cancer cells with
range of thyroid and ovarian cancer. acceptable side effects have been demonstrated (Li et al., 2013;
Pezzani et al., 2019). Thus, in recent years, the anticancer and
chemopreventive properties of phytochemicals are attracting
CONCLUSIONS AND FUTURE increasing interest from oncology researchers due to their low
PERSPECTIVES intrinsic toxicity in normal cells but prominent effects in
cancerous cells (Li et al., 2013).
Medicinal plants remain a crucial source in the search and In this review, an attempt has been made to provide a
development of new pharmacological leads. One major asset of database of phytochemicals that are used for in vivo and
medicinal plant-based drug discovery is the existence of clinical studies. This information will be extremely useful to

identify a series of additional plant-derived drugs to treat ACKNOWLEDGMENTS

cancer with minimum side effects.
AC (File No: PDF/2016/003615) is grateful to the Science
and Engineering Research Board (SERB), Government of
AUTHOR CONTRIBUTIONS India, New Delhi for the award of a National Post-Doctoral
Fellowship. Om Prakash is thankful to the Stanley S. Scott
OP and PR made substantial contributions to conception and Cancer Center for providing financial support for the
design of the article. AC, PM, and MD contributed to the writing preparation and publication of this article. The
and editing of the manuscript. AC and PM contributed to the authors are thankful to Adam Lassak and Suman Prakash
designing of the figures and tables. All the authors read and for their help in revising, editing, and formatting the
approved the final manuscript for publication. citation list.
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Phytochemicals in Cancer Treatment From Preclinical Studies To Clinical Practice

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published: 28 January 2020

Phytochemicals in Cancer Treatment:

Frontiers in Pharmacology | www.frontiersin.org 1 January 2020 | Volume 10 | Article 1614

PLANT DERIVED DRUGS: A HISTORICAL PHYTOCHEMICALS WITH ANTICANCER

TABLE 1 | List of commercially available plant derived drugs on various diseases.

Drug Class of drug Plant source Disease Reference

COPD, chronic obstructive pulmonary disease.

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FIGURE 1 | Chemical structures of some anticancer phytochemicals in preclinical trials.

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TABLE 2 | Phytochemicals in pre-clinical trials for cancer treatment.

Phytochemical Botanical name (family) Molecular targets Reference

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FIGURE 2 | Chemical structures of some anticancer agents in clinical trials.

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TABLE 3 | List of phytochemicals currently in clinical trial on various cancers.

Phytochemical Class of com- Type of cancer Assessment Reference

Berberine Berberis sp. Colorectal cancer Prevention of recurrence NCT03281096*

*Indicates reference found at www.clinicaltrials.gov with corresponding identiﬁer code (NCT).

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FIGURE 3 | Chemical structures of some anticancer agents in clinical use.

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TABLE 4 | Compounds used for cancer treatment.

Class of phyto- Pharmacological action Type of cancer Molecular

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identify a series of additional plant-derived drugs to treat ACKNOWLEDGMENTS

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