Indonesian Journal of Cancer Chemoprevention, February 2018

ISSN: 2088–0197
e-ISSN: 2355-8989

Revealing the Potency of Cinnamon

as an Anti-Cancer and Chemopreventive Agent

Yonika Arum Larasati and Edy Meiyanto*

Cancer Chemoprevention Research Center, Faculty of Pharmacy,

Universitas Gadjah Mada, Yogyakarta, Indonesia

Abstract

Cinnamon (Cinnamomum spp.), an ancient spice, has been explored as a potential for medicinal
purposes. Despite numerous studies about its potency in overcoming of numerous diseases, the
potency as anti-cancer would be a challenge. This current article provides a review of the anti-
cancer and chemoprevention potency of cinnamon and its major constituents: cinnamaldehyde,
cinnamic acid, 2-hydroxycinnamaldehyde, 2-methoxycinnamaldehyde, and eugenol. Comprehensively,
cinnamon and its constituents exhibit the anti-cancer and cancer prevention activities through
various mechanisms: (1) anti-proliferation, (2) induction of cell death, (3) anti-angiogenesis, (4) anti-
metastasis, (5) suppression of tumor-promoted inflammation, (6) immunomodulation, and (7)
modulation of redox homeostasis; both in vitro and in vivo. Moreover, cinnamon also shows the
synergistic anti-cancer effect with well-known anti-cancer drugs, such as doxorubicin, which support
its potency to be used as a combination chemotherapeutic (co-chemotherapeutic) agent. However,
further study should be established to determine the exact target molecule(s) of cinnamon in the
cancer cells.

Keywords: cinnamon, spice, cancer, anti-cancer, chemopreventive

membrane translocation of glucose transporter-4,

INTRODUCTION stimulating glucose metabolism and glycogen
synthesis; and in vivo, including reducing fasting
Cinnamon has been widely used in either the blood glucose and increasing circulating insulin
East or West parts of the world as a spice for levels. Another biological activity of cinnamon is the
thousands of years. Originally from Ceylon (Sri gastro-protective effect, which is attributed to
Lanka), cinnamon spreads around the world through cinnamon activity as an anti-inflammatory and anti-
trading and colonization (Barceloux, 2009). The ulcer agent (Yu, et al., 2012; Alqasoumi 2012). A
genus Cinnamomum is made up of more than 250 pharmaceutical company in Indonesia, Dexa Medica,
species, which primarily cultivated in Asia and steps up the value of cinnamon by using it as the
Australia. Some of the most valuable and famous active ingredient of their drugs. Dexa Medica has
species are Cinnamomum zeylanicum (Sri formulated the standardized extract of C. burmanni
Lanka/Ceylon cinnamon), Cinnamomum cassia into Inlacin® and Redacid® with the indication as
(China cinnamon), and Cinnamomum burmanni an anti-diabetic and gastro-protector, respectively.
(Indonesia cinnamon). Ranasinghe, et al. (2013) provided a
Cinnamon bark is the most common part to be comprehensive systematic review regarding
used from a cinnamon tree. Numerous studies have cinnamon biological activities, including a) anti-
been conducted to reveal the biological activity of microbial and anti-parasitic activity, b) lowering of
cinnamon. One of the most well studied is the
potency of cinnamon as an anti-diabetic agent. As
reviewed by Ranasinghe, et al. (2012), C. Submitted: Feb 20, 2018
Revised: Feb 21, 2018
zeylanicum showed an anti-diabetic activity in vitro, Accepted: Feb 22, 2018
such as stimulating cellular glucose uptake by
*
Corresponding author e-mail : [email protected]
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Indones. J. Cancer Chemoprevent., 9(1), 47-62

blood glucose, blood pressure, and serum extraction or distillation, yielded in aqueous extract
cholesterol, c) antioxidant and free-radical or essential oil, respectively. Using both methods,
scavenging properties, d) inhibition of tau cinnamaldehyde/ trans-cinnamaldehyde/ cinnamic
aggregation and filament formation (hallmarks of aldehyde remains as the main constituent of
Alzheimer’s disease), e) inhibitory effects on osteo- cinnamon bark. Ding, et al. (2011) analyzed the
clastogenesis, f) anti-secretagogue and anti-gastric content of cinnamon barks and twigs and found
ulcer effects, g) anti-nociceptive and anti- cinnamaldehyde as the most abundant marker
inflammatory activity, h) wound healing properties component (average content was 86.25 mg/g),
and i) hepato-protective effects. Yet, in spite of followed by eugenol (14.40 mg/g), coumarin (5.79
numerous research reported the activity of cinnamon mg/g), cinnamyl alcohol (1.13 mg/g), and cinnamic
as an anti-cancer agent, to date there is no acid (0.87 mg/g).
comprehensive review in this topic. Therefore, here In addition to those compounds, they also
we review the recent original research articles found 2-hydroxyl cinnamaldehyde, cinnamyl
studying cinnamon and/or its constituent effect on alcohol, and 2-methoxy cinnamaldehyde in the
various models of cancer. This review article aims to sample. Another study by Kamaliroosta, et al.
provide an overview regarding the activity cinnamon (2012) found that the essential oil of cinnamon barks
and its chemical constituents as an anti-cancer and (C. zeylanicum) comprises of cinnamic aldehyde
chemopreventive agent. Furthermore, we discuss the (62.09 %), para-methoxycinnamic aldehyde
molecular targets of cinnamon in cancer cells in (11.56%), alpha-copaene (6.98%), and alpha-
order to provide a deeper and comprehensive muurolene (4.32%) as the main constituents. In this
understanding of cinnamon potency as an anti- current article, we discuss several unique
cancer and chemopreventive agent. constituents of cinnamon bark that have been studied
as the anti-cancer and chemopreventive agents,
CONSTITUENTS OF CINNAMON BARK which are cinnamaldehyde, cinnamic acid, 2-
hydroxycinnamaldehyde, 2-metho-
The most common method to extract the xycinnamaldehyde, and eugenol (Fig. 1).
constituent of cinnamon bark is by either water

Cinnamaldehyde Cinnamic acid

2-hydroxycinnamaldehyde 2-methoxycinnamaldehyde

Eugenol

Figure 1. Chemical constituents of cinnamon bark that have been studied as the anticancer and
chemopreventive agent

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ANTI-CANCER ACTIVITIES OF metabolism. In addition to those mentioned features,

CINNAMON BARK scientists also consider redox homeostasis in the
cancer cells to be a target for cancer therapy. Redox
Cancer is a disease with multiple homeostasis is the capacity of cells to manage the
physiological changes due to the complex genetic electrochemical potential inside the cells, which
alteration. A renowned review paper by Hanahan mostly related to the cells’ oxidative state (Wondrak,
and Weinberg in 2011 summarized the et al., 2009). Combination chemotherapy (co-
characteristics of cancer cells as following: (1) chemotherapy) is also in well-known strategy that
sustaining proliferative signaling; (2) evading works by combining two or more anti-cancer or
growth suppressor; (3) avoiding immune destruction; chemopreventive agent in order to increase the
(4) enabling replicative immortality; (5) tumor- efficacy of cancer therapy and/or alleviate the side
promoting inflammation; (6) activating invasion and effect of cancer therapy.
metastasis; (7) inducing angiogenesis; (8) genome Researchers have conducted myriad studies
instability and mutation; (9) resisting cell death; and on the anti-cancer potency of cinnamon bark. The
(10) deregulating cellular energetics (Hanahan and summary of anti-cancer activities of extract and/or
Weinberg, 2011). In general, cancer cells are able to essential oil of cinnamon bark is available in the
grow uncontrollably, escaping cell death and Table 1; while the summary of anti-cancer activities
immune destruction, invade tissues and metastasize, of the chemical constituents of cinnamon bark is
induce angiogenesis, promote inflammation in available in the Table 2.
surrounding tissues, and has aberrant cell

Table 1. Anti-cancer activity of cinnamon extract/essential oil

Preparation of Physiology/cellular effect Molecular event(s) Reference

extract/ as anti-cancer
essential oil
- AEC inhibits melanoma - Down-regulates the Kwon, et al. (2009)
progression in vivo level of pro-
- AEC inhibits tumor angiogenesis in angiogenic factors
vivo (EGF, VEGF-α, TGF-
- AEC increases the cytolytic activity b, and FGF)
of CD8+ T cells in tumor draining - Down-regulates the
lymph nodes. level of HIF-1α and
COX-2
- AEC inhibits tumor cell growth (in - Down-regulates both Kwon, et al. (2010)
HeLa, Caco-2, EL4, and Clone M3 activity and
cell lines) in vitro, but not in normal expression level of
cells (primary mouse lymphocyte) NFκB and AP1
- AEC inhibits tumor cell growth in - Inhibits the
aqueous extract of
vivo expression of anti-
C. cassia (AEC)
apoptotic proteins
(Bcl-2, BcL-xL and
survivin)
- AEC inhibits SiHa cervical cancer - Decreases the Koppikar, et al. (2010)
cells growth and migration expression of MMP-2
- AEC induces apoptosis in SiHa and HER2
cells - Decreases
mitochondrial
membrane potential
- AEC inhibits angiogenesis in - Decreases TPA- Bansode, et al. (2013)
HUVEC cells and zebrafish embryo induced PKCα and
PKCγ mRNA
expression

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Indones. J. Cancer Chemoprevent., 9(1), 47-62

- Decreases VEGFR1
and VEGFR2 mRNA
expression
- Inhibits the
phosphorylation of
MAPK signaling
cascade
aqueous extract of - AEB inhibits the proliferation of - Decreases the Schoene, et al. (2005)
Cinnamomum myeloid cell lines (Jurkat, intracellular
Burmannii Wurzburg, and U937 cells) phosphatase activity
(AEB) - AEB induced G2/M arrest in
myeloid cells
- AEZ shows higher cytotoxic Not determined Singh, et al. (2009)
activity compared to commercial
aqueous extract of cinnamaldehyde (at comparable
Cinnamomum concentraton of cinnamaldehyde)
zeylanicum in various cancer cell lines
(AEZ) - In the toxic dose, AEZ shows
significant higher cytotoxicity in
cancer cells rather than in normal
cell
- EOB shows cytotoxicity and Not determined Anjarsari, et al. (2013)
Essential oil of
induces apoptosis in T47D breast Larasati, et al. (2014)
Cinnamomum
cancer cells and HeLa cells
burmannii
- EOB shows synergist effect with
(EOB)
doxorubicin in T47D cells and with
cisplatin in HeLa cells
- EC inhibits the proliferation of HT- - Decreases the Lee, et al. (2006)
29 colon cancer cells, but not production of PGE2
Ethanol extract of
CCD-112CoN normal colon cells - Decreases the
cinnamon (EC)
expression of
COX-2
AP1: activator protein 1; Bcl-2: B-cell lymphoma 2; Bcl-xL: B-cell lymphoma-extra large; COX-2: cyclooxygenase 2; EGF: epidermal growth
factor; FGF: fibroblast growth factor; HER2: human epidermal growth factor receptor 2; HUVEC: human umbilical vein endothelial cells;
MAPK: mitogen-activated protein kinase; MMP-2: matrix metalloproteinase-2; mRNA: messenger ribonucleic acid; NFκB: nuclear factor
kappa B; PGE2: prostaglandin E2; PKCα: protein kinase C-α; PKCγ: protein kinase C-γ; TGF-β: transforming growth factor-β; VEGF-α:
vascular endothelial growth factor-α; VEGFR1: vascular endothelial growth factor receptor 1; VEGFR2: vascular endothelial growth factor
receptor 2.

Table 2. Anti-cancer activity of the constituents of cinnamon bark

Compound Physiology/cellular effect Molecular event(s) Reference

as anti-cancer
- CA inhibits the proliferation and - Increases ROS Ka, et al. (2003)
induces apoptosis in HL60 pro- intracellular
myelocytic leukemia cells
- CA exhibits cytotoxicity in Jurkat - Not determined Fang, et al. (2004)
Cinnamaldehyde / and U397 leukemia cells, but not in
trans- normal T cells and macrophages
cinnamaldehyde/ - CA induces G2/M arrest in Jurkat
cinnamic aldehyde/ and U397 leukemia cells
(CA) - CA suppresses the proliferation of - Increases intracellular Cabello, et al. (2009)
human metastatic melanoma cell ROS
lines (A375, G361, LOX) with G1 - Up-regulates HMOX1,
cell cycle arrest in vitro SRXN1, TXNRD1,
- CA inhibits tumor progression in vivo CDKN1A

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- CA treatment at low micromolar - Inhibits of NFκB

concentrations up-regulates transcriptional activity
oxidative stress response gene and TNFα-induced IL-8
expression in A375 melanoma production
cells
- CA induces apoptosis in K562 - Up-regulates Fas Zhang, et al. (2010)
leukemia cells expression
- CA exhibits synergist cytotoxicity - Decreases
with cytokine-induced killer (CIK) mitochondrial
cells transmembrane
potential
- CA inhibits the proliferation and - Inhibits thioredoxin Chew, et al. (2010)
induces apoptosis in HCT116 colon reductase enzymatic
cancer and MCF-7 breast cancer activity
cells - Induces Nrf2 activity
- CA induces G2/M arrest in HCT116
cells
- CA exhibits cytotoxicity in colon - Up-regulates the Nrf2 Wondrak, et al.
cancer cells activity (2010)
- Pre-treatment with CA attenuates - Up-regulates heme
H2O2-induced genotoxicity in colon oxygenase 1 (HO-1)
cancer cells and γ-glutamylcysteine
synthetase (γ-GCS,
catalytic subunit)
- Up-regulates cellular
glutathione level
- CA induces apoptosis and G2/M - Down-regulates Cdk1 Nagle, et al. (2012)
arrest in HCT116 cells and cdc25
- CA induces tubulin aggregation - Up-regulates the level
of cyclin B
- CA inhibits the proliferation and - Decreases the Chuang, et al. (2012)
induces apoptosis in HepG2 and expression of cyclin D1,
Hep3B hepatoma cells PCNA, and Bcl-2
- Induces the expression
of p27 and p21
- Activates caspase-3
- Inhibits JAK2–
STAT3/STAT5 signaling
pathway
- CA shows higher cytotoxicity than - Induces Daker, et al. (2013)
cisplatin in C666-1 human phosphorylation of
nasopharyngeal carcinoma (NPC) histone H2AX
cells - Induces activation of
- CA shows synergist anti-proliferative caspase-3/7
effect with cisplatin
- CINN inhibits the invasiveness of - Inhibits the activity of Yen, et al. (2011)
A549 lung adenocarcinoma cells MMP-2 and MMP-9
without significant effect on the
adhesive activity of cells
- cis-cinnamic acid shows higher
activity than trans-cinnamic acid
Cinnamic acid - CINN pre-treatment reduces - Reduces lipid Patra, et al. (2012)
(CINN) cyclophosphamide-induced peroxidation
myelosuppression and oxidative - Increases the activity of
stress in bone marrow antioxidant enzymes
(superoxide dismutase,
catalase and

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Indones. J. Cancer Chemoprevent., 9(1), 47-62

glutathione-S-
transferase)
- CINN inhibits the invasiveness of - Inhibits the activity of Tsai, et al. (2013)
A549 lung adenocarcinoma cells MMP-2 and MMP-9
- Increases the levels of
PAI-2 to suppress uPA
activity
- Supresses NFκB and
AP-1
- CINN inhibits the proliferation of - Down-regulates Bcl-2 Huang, et al. (2012)
lung cancer stem cells and survivin
- CINN induces G1 arrest and - Up-regulates Bax
apoptosis in lung cancer stem cells
- CINN increases the sensitivity of
lung cancer stem cells toward
cisplatin and paclitaxel
- CINN promotes differentiation and
reduces the invasive ability of lung
cancer stem cells
- CINN induces cytotoxicity and - Increases the activation de Oliveira Niero and
apoptosis in human melanoma cell of caspase-3 and Machado-Santelli
line (HT-144) expression of Bax (2013)
- Decreases the
expression of Bcl-2
- 2-HCA induces apoptosis in SW620 - 2-HCA binds to 5 Hong, et al. (2007)
colon cancer cells subunits of proteasome
complex and inhibits
the activity of
proteasome
- Induces ER stress
- Decreases
mitochondrial
membrane potential
- 2-HCA inhibits the growth and - Inhibits AP-1 Lee, et al. (2007)
induces apoptosis in SW 620 human transcriptional activity
colon cancer cell and DNA binding
activity
- Inhibits c-Jun and c-Fos
expression
2-
- Increases caspase-3 and
hydroxycinnamalde
decreases Bcl-2
hyde
- 2-HCA inhibits oral cancer growth in - Increases the levels of Kim, et al. (2010)
(2-HCA)
vitro and in vivo cleaved PARP and
- 2-HCA induces apoptosis and cell caspase-3
cycle arrest in G2/M phase
- 2-HCA inhibits the proliferation of - Inhibits thioredoxin Chew, et al. (2010)
HCT116 colon cancer and MCF-7 reductase enzymatic
breast cancer cells activity
- 2-HCA inhibits breast cancer cell - Increases E-cadherin Ismail, et al. (2013)
migration without affecting viability transcription
- 2-HCA inhibits EGF-induced EMT in - Suppresses the protein
breast cancer cells level of Snail
- 2-HCA inhibits lung metastasis and - Induces KLF17
micromestastasis in vivo expression
- Suppresses SP-1 and ID-
1 expression

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- 2-HCA inhibits the proliferation of - Inhibits Wnt/β-catenin Lee, et al. (2013)

HCT116 colon cancer cells transcriptional activity
- 2-HCA suppressed tumor growth in - Decreases the mRNA
vivo level of CCND1, CMYC,
MMP7, PLAU, XIN2,
NKD1, and DKK1
- 2-MCA inhibits the proliferation of - Not determined Chew, et al. (2010)
2- HCT116 colon cancer and MCF-7
methoxycinnamalde breast cancer cells
hyde - 2-MCA inhibits tumor growth via - Inhibits the Yamakawa, et al.
(2-MCA) inhibition of angiogenesis in vivo phosphorylation of Tie2 (2011)
- 2-MCA inhibits the maturation of
tumor vasculature
- Eugenol showed a dose-dependent - downregulation of Bcl-2, Hussain, et al. (2011)
selective cytotoxicity toward HeLa COX-2, and IL-1β
cells in comparison to normal cells
- Eugenol exhibits synergist anti-
cancer effect with gemcitabine in
HeLa cells
- Eugenol exhibits cytotoxicity and - Depletes MMP Jaganathan, et al.
induces apoptosis in colon cancer - Generates ROS (2011)
cells - Activates PARP, p53 and
caspase-3
- Eugenol significantly reduces the - Suppresses of NFκB Manikandan et al.
incidence of MNNG-induced gastric activation (2011)
tumours - Down-regulates NF-κB
Eugenol
target genes (cyclin D1,
Cyclin B, PCNA, and
Gadd45)
- Eugenol shows cytotoxicity in breast - Inhibits the expression Al-Sharif, et al. (2013)
cancer cells and less toxic in non- of p65 NFκB, β-catenin,
neoplastic breast epithelial cells cyclin D1, survivin, and
- Eugenol induces apoptosis in breast E2F1.
cancer cells - Activates pro-apoptosis
- Eugenol inhibits tumor growth of protein: caspase-3,
breast tumor in vivo caspase-1, cytochrome c,
caspase-9
- Up-regulates p21

AP1: activator protein 1; Bcl-2: B-cell lymphoma 2; Bax: Bcl-2 Associated X; COX-2: cyclooxygenase 2; CCND1: cyclin D1 (gene); Cdk1:
cyclin dependent kinase 1; CDKN1A: cyclin-dependent kinase inhibitor 1A (gene); DKK1: Dickkopf-related protein 1; DNA:
deoxyribonucleic acid; EGF: epidermal growth factor; EMT: epithelial-mesenchymal transition; ER: endoplasmic reticulum; E2F1: E2 factor-
transcription factor 1; GADD45: growth arrest and DNA-damage-inducible protein 45 alpha; γ-GCS: γ-glutamylcysteine synthetase; HO-
1: heme oxygenase 1 (protein); HMOX1: heme oxygenase-1 (gene); H2O2: hydrogen peroxide; Id-1: inhibitor of differentiation/DNA
binding; IL-8: interleukin 8; IL-1β: interleukin 1β; JAK: Janus tyrosine Kinase; KLF17: Kruppel Like Factor 17; MMP-2: matrix
′
metalloproteinase-2; MMP-9: matrix metalloproteinase-9; MMP7: matrix metalloproteinase-7; MNNG: N-methyl-N -nitro-N-
nitrosoguanidine; NKD: naked cuticle homolog 1; NFκB: nuclear factor kappa B; Nrf2: nuclear factor erythroid 2 (NFE2)-related factor 2;
PAI2: plasminogen activator inhibitor-2; PARP: poly (ADP-ribose) polymerase; PCNA: proliferating cell nuclear antigen; PLAU: plasminogen
activator, urokinase; ROS: reactive oxygen species; SRXN1: sulfiredoxin 1 homolog; STAT: Signal Transducer and Activator of
Transcription; Sp1: specificity protein 1; TNFα: tumor necrosis factor α; TXNRD1: thioredoxin reductase 1; uPA: urokinase-type
plasminogen activator; VEGFR2: vascular endothelial growth factor receptor 2.

ANTI-PROLIFERATIVE AND PRO- (anti-proliferative) and cell death-inducer (pro-

APOPTOSIS apoptosis). The activity of cinnamon bark and/or its
The most well-known and traditional anti- constituents as the anti-proliferative and pro-
cancer drugs act as tumor cell growth suppressor apoptosis are presented below.

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Cinnamon extract/essential oil cinnamaldehyde also suppresses tumor cell

Aqueous extract of C. cassia (AEC) exhibits progression in vivo in the mouse model of cancer
an anti-proliferative effect in vitro and in vivo in (Cabello, et al., 2009).
various models of cancer, such as melanoma, Suppression of cancer cell growth can be
cervical cancer, and colon cancer (Kwon, et al., attributed to the inhibition of cell division (cell
2009; Kwon, et al., 2010; Koppikar, et al., 2010). cycle) and/or induction of cell death.
Koppikar, et al. (2010) found that AEC increases Cinnamaldehyde induces G1 cell cycle ar,rest in
intracellular levels of calcium, leads to perturbation melanoma cells (Cabello, et al., 2009). However,
of mitochondrial membrane potential, which other studies found that cinnamaldehyde induces
ultimately induces apoptosis in SiHa cervical cancer G2/M arrest in Jurkat and U397 leukemia cells; as
cells. Another study by Kwon, et al. (2010) found well as HCT116 colon cancer cells (Fang, et al.,
that AEC also suppresses the expression of anti- 2004;, Chew, et al., 2010; Nagle, et al., 2012).
apoptotic proteins (e.g., Bcl-2, BcL-xL, and Nagle, et al. (2012) reported several molecular
survivin) by down-regulating the activity and events by which cinnamaldehyde induces G2/M
expression level of NFκB and AP1 proteins. arrest. Cinnamaldehyde down-regulates protein
Another species of cinnamon, C. burmannii, Cdk1 and cdc25, which are the important proteins
also exhibits anti-cancer potency. Schoene, et al. for G2/M progression. Cyclin B, an important
(2005) reported that the aqueous extract of C. protein that should be diminished during G2/M
burmannii (AEB) inhibits the proliferation of some progression, was sustained by cinnamaldehyde.
myeloid cell lines: Jurkat, Wurzburg, and U937 Moreover, cinnamaldehyde induces tubulin
cells). AEB decreases the intracellular phosphatase aggregation; hence the cells in G2/M phase can not
activity that later induces cell cycle arrest in G2/M further divide themselves.
phase. In addition, the essential oil of C. burmannii In addition to the induction of cell cycle
shows cytotoxicity and induces apoptosis in T47D arrest, cinnamaldehyde induces apoptosis in
breast cancer cells (Anjarsari, et al., 2013). leukemia, colon cancer, breast cancer, hepatoma,
Interestingly, cinnamon bark shows selective and human nasopharyngeal carcinoma (NPC) cells
anti-proliferative effect towards cancerous cells (Ka, et al., 2003; Zhang, et al., 2010; Chew, et al.,
rather than normal (non-cancerous) cells. Lee, et al. 2010; Chuang, et al., 2012; Daker, et al., 2013).
(2006) reported that the extract of cinnamon inhibits Several mechanisms contribute to the apoptosis
the proliferation of HT-29 colon cancer cells, but not effect of cinnamaldehyde, such as generation of
CCD-112CoN normal colon cells. A similar result intracellular ROS (Ka, et al., 2003), up-regulation of
was reported by Kwon, et al. (2010); AEC inhibits cell death surface receptor Fas (Zhang, et al., 2010),
tumor cell growth (in HeLa, Caco-2, EL4, and Clone and modulation of pro- and anti-apoptosis proteins
M3 cell lines) in vitro, but not in normal cells (Chuang, et al., 2012; Daker, et al., 2013).
(primary mouse lymphocyte). Moreover, Singh, et
al. (2009) reported that the aqueous extract of C. Cinnamic acid
zeylanicum (AEZ) shows significant higher Cinnamic acid exhibits cytotoxicity and
cytotoxicity in cancer cells rather than in the normal induces apoptosis in HT-144 human melanoma
cells. This selectivity feature is very important for cells (de Oliveira Niero and Machado-Santelli,
the anti-cancer drugs that hopefully the drugs have 2013). Cinnamic acid up-regulates the activity of
minimum side effect for the clinical therapy. caspase-3 and expression of Bax, the pro-apoptotic
proteins; while decreasing the expression of Bcl-2,
Cinnamaldehyde an anti-apoptotic protein (de Oliveira Niero and
Cinnamaldehyde exhibits anti-proliferative Machado-Santelli, 2013). Interestingly, cinnamic
activity in various cancer cells, including leukemia acid also exhibits anti-cancer activity in the cancer
melanoma, colon cancer, nasopharyngeal carcinoma, stem cells. Huang, et al. (2012) examined the effect
breast cancer, and hepatoma in vitro (Ka, et al., of cinnamic acid in lung cancer stem cells.
2003; Fang, et al., 2004; Cabello, et al., 2009; Chew, Cinnamic acid inhibits the proliferation as well as
et al., 2010; Wondrak, et al., 2010; Chuang, et al., induces apoptosis and G1 arrest in the lung cancer
2012; Daker, et al., 2013). Moreover, stem cells.

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2-hydroxycinnamaldehyde (2-HCA) selectively toxic to cancer cells, but less toxic in

2- HCA shows the anti-proliferative activity normal cells. Hussain, et al. (2011) reported that
in colon cancer and oral cancer; as well as induces eugenol exhibits cytotoxicity in HeLa cervical
apoptosis in those cells (Hong, et al., 2007; Lee, et cancer cells, but not in normal cells. Another study
al., 2007; Kim, et al., 2010). Lee, et al. (2013) also by Al-Sharif, et al. (2013) showed that eugenol is
showed that 2-HCA inhibits tumor progression in more toxic in the breast cancer cells rather than in
vivo. Hong, et al. (2007) found that 2- non-neoplastic breast epithelial cells. Eugenol
hydroxycinnamaldehyde decreases mitochondrial induces apoptosis in cervical cancer, colon cancer,
membrane potential, resulting in cell apoptosis. Lee, and breast cancer cells in vitro (Hussain, et al., 2011;
et al. (2007) showed that 2-hydroxycinnamaldehyde Jaganathan, et al., 2011; Al-Sharif, et al., 2013).
modulates the pro- and anti-apoptotic protein levels, Eugenol also exhibits anti-tumor activity in vivo, in
such as caspase-3 and Bcl-2. In addition to rats developing MNNG-induced gastric tumors
apoptosis, 2-HCA induces cell cycle arrest in G2/M (Manikandan, et al., 2011) and breast cancer-
phase (Kim, et al., 2010). 2- HCA also inhibits the xenografted mice (Al-Sharif, et al., 2013).
transcriptional and DNA binding activity of AP-1, a At the molecular level, eugenol activates the
transcriptional factor important for cancer cell pro-apoptotic proteins, such as PARP, caspase-3,
growth (Lee, et al., 2007). caspase-1, and caspase-9; as well as up-regulates cell
2- HCA is the only constituent of cinnamon cycle regulator proteins p53 and p21 (Jaganathan, et
bark that has been studied for its direct protein target al., 2011; Al-Sharif, et al., 2013). Eugenol also
in cancer cells. Hong, et al. (2007) performed a suppresses the expression and activation of NFκB,
pull-down assay and found that 5 subunits of resulting in down-regulation of NF-κB target genes
proteasome complex interacted physically with 2- (cyclin D1, Cyclin B, PCNA, Gadd45)
hydroxycinnamaldehyde. This interaction inhibits (Manikandan, et al., 2011).
the activity of proteasome, resulting in various
perturbations inside the cancer cells, leading to ANGIOGENESIS
apoptosis. Even though not yet elucidating the direct To supply the nutrition and oxygen for their
binding site, Hong and colleague suggests that 2- growth, cancer cells form blood vessels in a process
hydroxycinnamaldehyde is an effective proteasome called angiogenesis. Hypoxia, a condition in which
inhibitor by inactivating multiple catalytic activities cancer cells lack of oxygen, plays a key role in
of proteasome. Another possible target of 2-HCA is angiogenesis; which then activates VEGF signaling
the Wnt/β-catenin pathway. Lee, et al. (2013) as the important mediator of angiogenesis (Hanahan
showed that 2-HCA inhibits the transcriptional and Weinberg, 2011). The activity of cinnamon bark
activity of Wnt/β-catenin. This inhibition results in and/or its constituents as an anti-angiogenic agent is
down-regulation of various gene targets of Wnt/β- discussed below.
catenin signaling, such as CCND1, CMYC, MMP7,
PLAU, XIN2, NKD1, and DKK1, which are the Cinnamon extract/essential oil
proteins that play role in cell proliferation, survival, Kwon, et al. (2009) reported that AEC
and motility. inhibits tumor angiogenesis in vivo and down-
regulates the level of pro-angiogenic factors (e.g.,
2-methoxycinnamaldehyde (2-MCA) EGF, VEGF-a, TGF-b, and FGF). They also found
2-MCA inhibits the proliferation of HCT116 that AEC decreases the level of HIF-1α, a
colon cancer cells (Chew, et al., 2010). However, transcription factor that is active in hypoxia
further study is needed to elucidate its exact condition and promote tumor angiogenesis. Another
molecular mechanism. study by Bansode, et al. (2013) reported that AEC
inhibits the formation of blood vessels in HUVEC
Eugenol cells and zebrafish embryo. More over, Bansode, et
Although not only found in cinnamon bark, al. showed that AEC inhibits the expression of PKC
eugenol is one of the major constituents of and inactivates MAPK/Akt signaling, which turns
cinnamon. An interesting feature of eugenol is that it out decreases the expression of VEGFR.

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2-methoxycinnamaldehyde (2-MCA) 2-hydroxycinnamaldehyde (2-HCA)

Yamakawa, et al. (2011) showed that 2-MCA Ismail, et al. (2013) reported the potency of 2-
suppresses tumor growth in vivo by inhibiting HCA as an anti-metastatic agent. They showed that
angiogenesis. Moreover, 2-MCA inhibits the sub-toxic dose of 2-HCA inhibits breast cancer cell
maturation of blood vessels in the tumor (tumor migration in vitro. 2-HCA also inhibits epidermal
vasculature). At the molecular level, 2-MCA inhibits growth factor (EGF)-induced epithelial-
the phosphorylation of Tie2, a vascular growth mesenchymal transition (EMT) in breast cancer
factor that is overexpressed in various tumors and cells. In vivo, 2-HCA is able to inhibit lung
induces angiogenesis. metastasis and suppress micro-metastasis.
At the molecular level, 2-HCA suppresses the
METASTASIS protein level of Snail, a transcriptional repressor of
In the onset of cancer, cancer cells starts to E-cadherin. Therefore, the transcription of E-
grow in the certain part of the body and become cadherin, a protein important protein for cell-cell
much more harmful once they spread to the other adhesion, is increased; resulting in the stronger cell-
parts of the body, in a process called metastasis cell integrity. Moreover, 2-HCA induces KLF17
(Hanahan and Weinberg, 2011). The metastasis expression. KLF17 is a repressor of Id-1, a protein
process consists of two steps: invasion and that increases the invasion of breast cancer cells.
migration. Matrix-metalloproteinase protein (MMP) Consequently, the 2-HCA decreases the expression
family mediates these processes by degrading the of Id-1 and inhibits breast cancer invasion.
extracellular matrix (ECM) proteins of the cells,
make it possible for cancer cells to sneak out their TUMOR-PROMOTED INFLAMMATION
original place and migrate to other parts of the body It was thought that the immune cells found in
(Deryugina and Quigley, 2006). The activity of the cancerous tissues aim to eradicate cancer cells
cinnamon bark and/or its constituents as an anti- inside the tissue. It turns out that those immune cells
metastatic agent is presented below. promote inflammation within the tumor. That
inflammation then provides the tumor
Cinnamon extract/essential oil microenvironment with various bioactive molecules,
Koppikar, et al. (2010) found that AEC including growth factors and pro-angiogenic factors
decreases the expression of MMP-2, both the mRNA (Hanahan and Weinberg, 2011). Inflammation also
and protein level, in SiHa cervical cancer cells. plays an important role in tumor initiation.
Furthermore, AEC also down-regulates the level of Therefore, an anti-inflammatory agent has the
HER-2 protein, an important marker in cervical potency to be developed as an anti-cancer and
cancer related to the invasion capacity of the tumor chemopreventive agent. The activity of cinnamon
cells. bark and/or its constituents as an anti-inflammatory
agent is discussed below.
Cinnamic acid
Yen, et al. (2011) and Tsai, et al. (2013) Cinnamon extract/essential oil
reported that cinnamic acid inhibits the invasive Kwon, et al. (2010) reported that AEC down-
ability of A549 lung adenocarcinoma cells. regulates the activity of NFκB, an important protein
Cinnamic acid decreases the mRNA level and for inflammation. In addition, Lee, et al. (2006)
activity of MMP-2 and MMP-9, as well as reported that the ethanol extract of cinnamon
suppresses the activity of NFκB and AP-1 (Tsai, et decreases the production of PGE2 and the expression
al., 2013). Moreover, cinnamic acid also reduces the of COX-2, two important mediators of
invasive ability of lung cancer stem cells (Huang, et inflammation.
al., 2013). Interestingly, the cis form of cinnamic
acid exhibits a better anti-metastatic activity Cinnamaldehyde
compared to the trans-cinnamic acid (Yen, et al., Several studies showed the anti-inflammatory
2011). activity of cinnamaldehyde in models other than

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cancer cells. Kim, et al. (2007) showed that Cinnamaldehyde

cinnamaldehyde inhibits the activation of NFκB via Ka, et al. (2003) reported that
three signal transduction pathways: NIK/IKK, ERK, cinnamaldehyde increases intracellular in HL60 pro-
and p38 MAPK. Cinnamaldehyde also blocks IL-1β- myelocytic leukemia cells. Another study by
induced PGE2 production in the mouse cerebral Cabello, et al. (2009) also showed that
microvascular endothelial cell (Ma, et al., 2008) and cinnamaldehyde increases the intracelullar reactive
mouse macrophage RAW264.7 cells (Zhang, et al., oxygen species (ROS) that leads to cancer cell death.
2012). Zhang, et al. also reported that However, at the sub-toxic dose, cinnamaldehyde up-
cinnamaldehyde suppresses the expression of PGE- regulates the oxidative stress response genes such as
synthase-1 (mPGES-1), an important inducer of heme oxygenase-1 (HMOX1), sulfiredoxin 1
PGE2 production. homolog (SRXN1), thioredoxin reductase 1
(TXNRD1). Moreover, Wondrak. et al. (2010) also
IMMUNOMODULATION reported a similar result. Wondrak and colleagues
The immune system is very important for found that cinnamaldehyde is a potent activator of
cancer elimination as it can help to fight cancer cells Nrf2 transciption. Sub-toxic concentration of
with no toxicity to normal tissue. However, the cinnamaldehyde (concentration range 6–10 μM)
problem arises as the eternal mutation in cancer cells strongly induced the transcription of Nrf2.
gives them the ability to evade the immune system.
Therefore, scientists develop some strategies to Cinnamic acid
utilize the components of immune system as cancer Patra, et al. (2012) showed the activity of
therapy, such as by directly targeting specific cinnamic acid as an antioxidant. Cinnamic acid
antigens expressed by cancer cells or targeting the increases the activity of antioxidant enzymes, such
immune system in the tumor microenvironment, as superoxide dismutase, catalase and glutathione-S-
such as cytokines, suppressors of Treg or MDSC transferase, as well as reduces lipid peroxidation.
activity, or antibodies that modulate T-cell activity
(Finn, et al., 2012). 2-hydroxycinnamaldehyde (2-HCA)
Cinnamon extract is able to modulate the Chew, et al. (2010) reported that 2-HCA
activity of T cells, the cytotoxic immune cells. AEC inhibits thioredoxin reductase enzymatic activity.
increases the increased the anti-tumor activities of
CD8+ T cells in tumor draining-lymph nodes Eugenol
(Kwon, et al., 2009). Kwon and colleagues found Jaganathan, et al. (2011) reported that eugenol
that AEC increases the cytolytic molecules (IFN-ϒ treatment elevates the intracellular ROS levels after
and TNF-α) expressed in the surface of CD8+ T 12 h and sustained until 48 h. Pre-treatment of
cells. Furthermore, AEC increases the killing cancer cells with n-acetyl-cysteine (NAC), a
activity of CD8+ T cells toward cancer cells. powerful antioxidant, blocked eugenol-induced
apoptosis. This result suggests that ROS is a key
REDOX HOMEOSTASIS IN CANCER player in eugenol activity as an anti-cancer agent.
CELLS
Redox homeostasis plays an important yet CO-CHEMOTHERAPY
complex role in the normal and cancer cells. The Combination chemotherapy (co-
main component of redox homeostasis is the reactive chemotherapy) is a strategy to increase the
oxygen species (ROS), which at the low level serves effectiveness of anti-cancer therapy by combining
as a mediator of signal transduction; while at the two or more anti-cancer agents. In addition, co-
high level disrupts various cell components, leading chemotherapy also aims to reduce the side effects of
to excessive mutations and/or cell death (Sosa, et al., a strong anti-cancer drug.
2013). Therefore, the level of intracellular ROS must
be regulated through a reliable redox system, which Cinnamon extract/essential oil
comprises of various enzymatic systems, such as Anjarsari, et al. (2013) found that the
glutathione redox system, thioredoxin system, and essential oil of C. burmannii (EOB) exhibits
Nrf2/Keap1-ARE pathway (Wondrak, et al., 2009). synergistic cytotoxic effect with doxorubicin in

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Indones. J. Cancer Chemoprevent., 9(1), 47-62

T47D breast cancer cells. This essential oil of EOB mechanisms of cinnamon constituents have been
also performs synergist effect with cisplatin to reported, only 2-hydroxycinnamaldehyde was shown
induce cell cycle arrest and apoptosis in HeLa cells to have direct protein target(s) by Hong, et al.
(Larasati, et al., 2014). This synergist activity is (2007). In this time of molecular targeted therapy,
expected to lower the dose of doxorubicin in cancer we need to elucidate more the direct target(s) of
clinical therapy. cinnamon constituents by using advanced
biomedical and medicinal chemistry approach in
Cinnamaldehyde order to pinpoint the exact anti-cancer mechanism of
Daker, et al. (2013) reported that those compounds.
cinnamaldehyde exhibits higher cytotoxicity than It is also interesting to note that compounds in
cisplatin in C666-1 human nasopharyngeal the cinnamon exhibit the different effect on the cell
carcinoma (NPC) cells. However, cinnamaldehyde redox homeostasis. Eugenol and 2-
also shows a synergist anti-cancer effect when hydroxycinnamaldehyde were reported to act as pro-
combined with cisplatin. Interestingly, oxidant agents that increase the level of intracellular
cinnamaldehyde also exhibits synergist cytotoxicity ROS and inhibit the cellular antioxidant enzymes
with cytokine-induced killer (CIK) cells toward (Chew, et al., 2010; Jaganathan, et al., 2011).
K562 leukemia cells (Zhang, et al., 2010). The CIK Cinnamic acid was reported as an antioxidant agent
cells resemble bone marrow transplantation that is (Patra, et al., 2012); while cinnamaldehyde was
usually performed in leukemia patients. Therefore, reported to promote the generation of intracellular
Zhang, et al. suggest that cinnamaldehyde is ROS, but also induce the activation of Nrf2 pathway
compatible to be used even in the leukemia patient (Ka, et al., 2003; Cabello, et al., 2009; Wondrak, et
with former bone marrow transplantation. al., 2010). An important factor to be noticed is the
dose used in those studies. Wondrak, et al. (2010)
Cinnamic acid used a relatively low dose of cinnamaldehyde (6–10
Patra, et al. (2012) reported that cinnamic μM) to induce the activation of Nrf2, which
acid pre-treatment protects bone marrow and hepatic practically did not show the toxic effect to the cancer
cells from cyclophosphamide-induced oxidative cells. On the other hand, Ka, et al. (2003) found that
stress. This activity of cinnamic acid occurs as it the IC50 value of cinnamaldehyde in HL60 cells is
induces the activity of antioxidant enzymes, such as 30.7 μM; while Cabello, et al. (2009) showed that
superoxide dismutase, catalase, and glutathione-S- cinnamaldehyde 25 μM exhibits cytotoxicity in the
transferase in the liver and bone marrow of mice, melanoma cells of >90%. These findings suggest
which counter the oxidative stress caused by that cinnamaldehyde exhibits bi-phasic activity in
cyclophosphamide. redox homeostasis of the cells: at low dose,
cinnamaldehyde triggers the activation of oxidative
FUTURE PROSPECT AND STRATEGY stress response system, such as Nrf2; while at the
high dose, cinnamaldehyde boosts the intracellular
After a thorough literature study, we found ROS level as one of its anti-cancer mechanism.
that the cinnamon and its constituents exhibit anti- Whether cinnamon and its constituents
cancer activities through various mechanisms, possess the anti- or pro-oxidant activities is
including anti-proliferation, pro-apoptosis, anti- important to be acknowledged with care. There are
angiogenesis, anti-metastasis, inhibition of tumor- developing evidence showed that antioxidant favors
induced inflammatory, immunomodulation, tumor growth. One of the important examples is
modulation of redox homeostasis, and combination Nrf2 pathway, the major arranger for various
chemotherapy. Astonishingly, despite its extensive enzymes that protect the cells from oxidative stress
anti-cancer mechanism, cinnamon selectively toxic (Kansanen, et al., 2013). While conventional studies
to the cancer cells rather than normal cells (Lee, et believe that Nrf2 pathway is important to protect the
al., 2006; Kwon, et al., 2010; Singh, et al., 2009); normal cells from being cancerous; current
which is an important feature for the development of developing studies reported that Nrf2 might play an
anti-cancer agents with less side effect. However, in important role in cancer chemoresistance and
spite of the diverse molecular anti-cancer enhancing cancer cell growth (Shibata, et al., 2008;

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Larasati, et al., 2018
Indones. J. Cancer Chemoprevent., 9(1), 47-62

Homma, et al., 2009). As reviewed by Kansanen, et VEGFR2, and PKC‐mediated MAP Kinase,
al. (2013), the Nrf2 activators are suitable to be used Food Sci. Nutr., 1(1), 74-82.
as in cancer prevention; while the Nrf2 inhibitors are Barceloux, D.G., 2009, Cinnamon (cinnamomum
suitable to be used in cancer therapy. Therefore, the species), Dis. Mon., 55(6), 327-335.
low dose cinnamaldehyde is appropriate to be used Cabello, C.M., Bair, W.B., Lamore, S.D., Ley, S.,
in cancer prevention; while the higher dose is needed Bause, A.S., Azimian, S., et al., 2009, The
for its use as the anti-cancer therapy. Considering Cinnamon-Derived Michael Acceptor
this topic, the cinnamon extract, which contains Cinnamic Aldehyde Impairs Melanoma Cell
various substances in moderate dosage, is more Proliferation, Invasiveness, and Tumor
suitable to be used as a chemopreventive agent. Growth, Free Radic. Biol. Med., 46(2), 220-
Meanwhile, the pure chemical constituents of 231.
cinnamon; such as cinnamaldehyde, cinnamic acid, Chew, E.H., Nagle, A.A., Zhang, Y., Scarmagnani, S.,
2-hydroxycinnamaldehyde, 2-metho- Palaniappan, P., Bradshaw, T.D., et al., 2010,
xycinnamaldehyde (2-MCA), and eugenol, are Cinnamaldehydes Inhibit Thioredoxin
potential to be developed as the anti-cancer agents. Reductase and Induce Nrf2: Potential
Candidates for Cancer Therapy and
CONCLUSION Chemoprevention, Free Radic. Biol. Med.,
48(1), 98-111.
Altogether, cinnamon and its constituent Chuang, L.Y., Guh, J.Y., Chao, L.K., Lu, Y.C., Hwang,
demonstrate potency to be used as the anti-cancer J.Y., Yang, Y.L., et al., 2012, Anti-proliferative
and chemopreventive agents. Nevertheless, further Effects of Cinnamaldehyde on Human
study needs to be conducted to determine the exact Hepatoma Cell Lines, Food Chem., 133(4),
molecular target(s) of cinnamon constituents. 1603-1610.
Finally, a meta-analysis review with more data and Daker, M., Lin, V.Y., Akowuah, G.A., Yam, M.F. and
statistical analysis would help to reveal the potency Ahmad, M., 2013, Inhibitory Effects of
of cinnamon to the greater extent. Cinnamomum Burmannii Blume Stem Bark
Extract and Trans-Cinnamaldehyde on
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