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Indonesian Journal of Cancer Chemoprevention, 2018, 9(1): 47-62
ISSN: 2088–0197
e-ISSN: 2355-8989
47
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
INTRODUCTION
Cinnamon has been widely used in either the
East or West parts of the world as a spice for
thousands of years. Originally from Ceylon (Sri
Lanka), cinnamon spreads around the world through
trading and colonization (Barceloux, 2009). The
genus Cinnamomum is made up of more than 250
species, which primarily cultivated in Asia and
Australia. Some of the most valuable and famous
species are Cinnamomum zeylanicum (Sri
Lanka/Ceylon cinnamon), Cinnamomum cassia
(China cinnamon), and Cinnamomum burmanni
(Indonesia cinnamon).
Cinnamon bark is the most common part to
be used from a cinnamon tree. Numerous studies
have been conducted to reveal the biological activity
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. zeylanicum
showed an anti-diabetic activity in vitro, such as
stimulating cellular glucose uptake by membrane
translocation of glucose transporter-4, stimulating
glucose metabolism and glycogen synthesis; and in
vivo, including reducing fasting blood glucose and
increasing circulating insulin levels. Another
biological activity of cinnamon is the gastro-
protective effect, which is attributed to cinnamon
activity as an anti-inflammatory and anti-ulcer agent
(Yu et al., 2012; Alqasoumi 2012). A
pharmaceutical company in Indonesia, Dexa Medica,
steps up the value of cinnamon by using it as the
active ingredient of their drugs. Dexa Medica has
formulated the standardized extract of C. burmanni
into Inlacin® and Redacid® with the indication as
an anti-diabetic and gastro-protector, respectively.
Ranasinghe et al. (2013) provided a
comprehensive systematic review regarding
cinnamon biological activities, including a) anti-
microbial and anti-parasitic activity, b) lowering of
blood glucose, blood pressure, and serum
cholesterol, c) antioxidant and free-radical
scavenging properties, d) inhibition of tau
aggregation and filament formation (hallmarks of
Alzheimer’s disease), e) inhibitory effects on osteo-
*Corresponding author e-mail : edy_meiyanto@ugm.ac.id
Larasati et al.
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clastogenesis, f) anti-secretagogue and anti-gastric
ulcer effects, g) anti-nociceptive and anti-
inflammatory activity, h) wound healing properties
and i) hepato-protective effects. Yet, in spite of
numerous research reported the activity of cinnamon
as an anti-cancer agent, to date there is no
comprehensive review in this topic. Therefore, here
we review the recent original research articles
studying cinnamon and/or its constituent effect on
various models of cancer. This review article aims to
provide an overview regarding the activity cinnamon
and its chemical constituents as an anti-cancer and
chemopreventive agent. Furthermore, we discuss the
molecular targets of cinnamon in cancer cells in
order to provide a deeper and comprehensive
understanding of cinnamon potency as an anti-
cancer and chemopreventive agent.
CONSTITUENTS OF CINNAMON BARK
The most common method to extract the
constituent of cinnamon bark is by either water
extraction or distillation, yielded in aqueous extract
or essential oil, respectively. Using both methods,
cinnamaldehyde/ trans-cinnamaldehyde/ cinnamic
aldehyde remains as the main constituent of
cinnamon bark. Ding et al. (2011) analyzed the
content of cinnamon barks and twigs and found
cinnamaldehyde as the most abundant marker
component (average content was 86.25 mg/g),
followed by eugenol (14.40 mg/g), coumarin (5.79
mg/g), cinnamyl alcohol (1.13 mg/g), and cinnamic
acid (0.87 mg/g). In addition to those compounds,
they also found 2-hydroxyl cinnamaldehyde,
cinnamyl alcohol, and 2-methoxy cinnamaldehyde in
the sample. Another study by Kamaliroosta et al.
(2012) found that the essential oil of cinnamon barks
(C. zeylanicum) comprises of cinnamic aldehyde
(62.09 %), para-methoxycinnamic aldehyde
(11.56%), alpha-copaene (6.98%), and alpha-
muurolene (4.32%) as the main constituents. In this
current article, we discuss several unique
constituents of cinnamon bark that have been studied
as the anti-cancer and chemopreventive agents,
which are cinnamaldehyde, cinnamic acid, 2-
hydroxycinnamaldehyde, 2-
methoxycinnamaldehyde, and eugenol (Figure 1).
Figure 1. Chemical constituents of cinnamon bark that have been studied as the anticancer and
chemopreventive agent
Cinnamic acid
Eugenol
Cinnamaldehyde
2-methoxycinnamaldehyde
2-hydroxycinnamaldehyde
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ANTI-CANCER ACTIVITIES OF
CINNAMON BARK
Cancer is a disease with multiple physiological
changes due to the complex genetic alteration. A
renowned review paper by Hanahan and Weinberg
in 2011 summarized the characteristics of cancer
cells as following: (1) sustaining proliferative
signaling; (2) evading growth suppressor; (3)
avoiding immune destruction; (4) enabling
replicative immortality; (5) tumor-promoting
inflammation; (6) activating invasion and metastasis;
(7) inducing angiogenesis; (8) genome instability
and mutation; (9) resisting cell death; and (10)
deregulating cellular energetics (Hanahan and
Weinberg, 2011). In general, cancer cells are able to
grow uncontrollably, escaping cell death and
immune destruction, invade tissues and metastasize,
induce angiogenesis, promote inflammation in
surrounding tissues, and has aberrant cell
metabolism. In addition to those mentioned features,
scientists also consider redox homeostasis in the
cancer cells to be a target for cancer therapy. Redox
homeostasis is the capacity of cells to manage the
electrochemical potential inside the cells, which
mostly related to the cells’ oxidative state (Wondrak
et al., 2009). Combination chemotherapy (co-
chemotherapy) is also in well-known strategy that
works by combining two or more anti-cancer or
chemopreventive agent in order to increase the
efficacy of cancer therapy and/or alleviate the side
effect of cancer therapy.
Researchers have conducted myriad studies on
the anti-cancer potency of cinnamon bark. The
summary of anti-cancer activities of extract and/or
essential oil of cinnamon bark is available in the
Table 1; while the summary of anti-cancer activities
of the chemical constituents of cinnamon bark is
available in the Table 2.
Table 1. Anti-cancer activity of cinnamon extract/essential oil
Preparation of
extract/
essential oil
Physiology/cellular effect
as anti-cancer
Molecular event(s)
Reference
aqueous extract of
C. cassia (AEC)
- AEC inhibits melanoma
progression in vivo
- AEC inhibits tumor angiogenesis in
vivo
- AEC increases the cytolytic activity
of CD8+ T cells in tumor draining
lymph nodes.
- Down-regulates the
level of pro-
angiogenic factors
(EGF, VEGF-α, TGF-
b, and FGF)
- Down-regulates the
level of HIF-1α and
COX-2
Kwon et al. (2009)
- AEC inhibits tumor cell growth (in
HeLa, Caco-2, EL4, and Clone M3
cell lines) in vitro, but not in normal
cells (primary mouse lymphocyte)
- AEC inhibits tumor cell growth in
vivo
- Down-regulates both
activity and
expression level of
NFκB and AP1
- Inhibits the
expression of anti-
apoptotic proteins
(Bcl-2, BcL-xL and
survivin)
-
Kwon et al. (2010)
- AEC inhibits SiHa cervical cancer
cells growth and migration
- AEC induces apoptosis in SiHa
cells
- Decreases the
expression of MMP-2
and HER2
- Decreases
mitochondrial
membrane potential
Koppikar et al. (2010)
- AEC inhibits angiogenesis in
HUVEC cells and zebrafish embryo
- Decreases TPA-
induced PKCα and
PKCγ mRNA
Bansode et al. (2013)
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expression
- Decreases VEGFR1
and VEGFR2 mRNA
expression
- Inhibits the
phosphorylation of
MAPK signaling
cascade
aqueous extract of
Cinnamomum
Burmannii
(AEB)
- AEB inhibits the proliferation of
myeloid cell lines (Jurkat,
Wurzburg, and U937 cells)
- AEB induced G2/M arrest in
myeloid cells
- Decreases the
intracellular
phosphatase activity
Schoene et al. (2005)
aqueous extract of
Cinnamomum
zeylanicum
(AEZ)
- AEZ shows higher cytotoxic
activity compared to commercial
cinnamaldehyde (at comparable
concentraton of cinnamaldehyde)
in various cancer cell lines
- In the toxic dose, AEZ shows
significant higher cytotoxicity in
cancer cells rather than in normal
cell
Not determined
Singh et al. (2009)
Essential oil of
Cinnamomum
burmannii
(EOB)
- EOB shows cytotoxicity and
induces apoptosis in T47D breast
cancer cells and HeLa cells
- EOB shows synergist effect with
doxorubicin in T47D cells and with
cisplatin in HeLa cells
Not determined
Anjarsari et al. (2013)
Larasati et al. (2014)
Ethanol extract of
cinnamon (EC)
- EC inhibits the proliferation of HT-
29 colon cancer cells, but not
CCD-112CoN normal colon cells
- Decreases the
production of PGE2
- Decreases the
expression of
COX-2
Lee et al. (2006)
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
as anti-cancer
Molecular event(s)
Reference
Cinnamaldehyde /
trans-
cinnamaldehyde/
cinnamic aldehyde/
(CA)
- CA inhibits the proliferation and
induces apoptosis in HL60 pro-
myelocytic leukemia cells
- Increases ROS
intracellular
Ka et al. (2003)
- CA exhibits cytotoxicity in Jurkat
and U397 leukemia cells, but not in
normal T cells and macrophages
- CA induces G2/M arrest in Jurkat
and U397 leukemia cells
- Not determined
Fang et al. (2004)
- CA suppresses the proliferation of
human metastatic melanoma cell
- Increases intracellular
ROS
Cabello et al. (2009)
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lines (A375, G361, LOX) with G1
cell cycle arrest in vitro
- CA inhibits tumor progression in vivo
- CA treatment at low micromolar
concentrations up-regulates
oxidative stress response gene
expression in A375 melanoma cells
- Up-regulates HMOX1,
SRXN1, TXNRD1,
CDKN1A
- Inhibits of NFκB
transcriptional activity
and TNFα-induced IL-8
production
- CA induces apoptosis in K562
leukemia cells
- CA exhibits synergist cytotoxicity
with cytokine-induced killer (CIK)
cells
- Up-regulates Fas
expression
- Decreases
mitochondrial
transmembrane
potential
Zhang et al. (2010)
- CA inhibits the proliferation and
induces apoptosis in HCT116 colon
cancer and MCF-7 breast cancer
cells
- CA induces G2/M arrest in HCT116
cells
- Inhibits thioredoxin
reductase enzymatic
activity
- Induces Nrf2 activity
Chew et al. (2010)
- CA exhibits cytotoxicity in colon
cancer cells
- Pre-treatment with CA attenuates
H2O2-induced genotoxicity in colon
cancer cells
- Up-regulates the Nrf2
activity
- Up-regulates heme
oxygenase 1 (HO-1)
and γ-glutamylcysteine
synthetase (γ-GCS,
catalytic subunit)
- Up-regulates cellular
glutathione level
Wondrak et al. (2010)
- CA induces apoptosis and G2/M
arrest in HCT116 cells
- CA induces tubulin aggregation
- Down-regulates Cdk1
and cdc25
- Up-regulates the level
of cyclin B
Nagle et al. (2012)
- CA inhibits the proliferation and
induces apoptosis in HepG2 and
Hep3B hepatoma cells
- Decreases the
expression of cyclin D1,
PCNA, and Bcl-2
- Induces the expression
of p27 and p21
- Activates caspase-3
- Inhibits JAK2–
STAT3/STAT5 signaling
pathway
Chuang et al. (2012)
- CA shows higher cytotoxicity than
cisplatin in C666-1 human
nasopharyngeal carcinoma (NPC)
cells
- CA shows synergist anti-proliferative
effect with cisplatin
- Induces
phosphorylation of
histone H2AX
- Induces activation of
caspase-3/7
Daker et al. (2013)
Cinnamic acid
- CINN inhibits the invasiveness of
A549 lung adenocarcinoma cells
without significant effect on the
- Inhibits the activity of
MMP-2 and MMP-9
Yen et al. (2011)
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(CINN)
adhesive activity of cells
- cis-cinnamic acid shows higher
activity than trans-cinnamic acid
- CINN pre-treatment reduces
cyclophosphamide-induced
myelosuppression and oxidative
stress in bone marrow
- Reduces lipid
peroxidation
- Increases the activity of
antioxidant enzymes
(superoxide dismutase,
catalase and
glutathione-S-
transferase)
Patra et al. (2012)
- CINN inhibits the invasiveness of
A549 lung adenocarcinoma cells
- Inhibits the activity of
MMP-2 and MMP-9
- Increases the levels of
PAI-2 to suppress uPA
activity
- Supresses NFκB and
AP-1
Tsai et al. (2013)
- CINN inhibits the proliferation of
lung cancer stem cells
- CINN induces G1 arrest and
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
-
- Down-regulates Bcl-2
and survivin
- Up-regulates Bax
Huang et al. (2012)
- CINN induces cytotoxicity and
apoptosis in human melanoma cell
line (HT-144)
- Increases the activation
of caspase-3 and
expression of Bax
- Decreases the
expression of Bcl-2
de Oliveira Niero and
Machado-Santelli
(2013)
2-
hydroxycinnamalde
hyde
(2-HCA)
- 2-HCA induces apoptosis in SW620
colon cancer cells
- 2-HCA binds to 5
subunits of proteasome
complex and inhibits
the activity of
proteasome
- Induces ER stress
- Decreases
mitochondrial
membrane potential
Hong et al. (2007)
- 2-HCA inhibits the growth and
induces apoptosis in SW 620 human
colon cancer cell
- Inhibits AP-1
transcriptional activity
and DNA binding
activity
- Inhibits c-Jun and c-Fos
expression
- Increases caspase-3 and
decreases Bcl-2
Lee et al. (2007)
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- 2-HCA inhibits oral cancer growth in
vitro and in vivo
- 2-HCA induces apoptosis and cell
cycle arrest in G2/M phase
- Increases the levels of
cleaved PARP and
caspase-3
Kim et al. (2010)
- 2-HCA inhibits the proliferation of
HCT116 colon cancer and MCF-7
breast cancer cells
- Inhibits thioredoxin
reductase enzymatic
activity
Chew et al. (2010)
- 2-HCA inhibits breast cancer cell
migration without affecting viability
- 2-HCA inhibits EGF-induced EMT in
breast cancer cells
- 2-HCA inhibits lung metastasis and
micromestastasis in vivo
- Increases E-cadherin
transcription
- Suppresses the protein
level of Snail
- Induces KLF17
expression
- Suppresses SP-1 and ID-
1 expression
Ismail et al. (2013)
- 2-HCA inhibits the proliferation of
HCT116 colon cancer cells
- 2-HCA suppressed tumor growth in
vivo
- Inhibits Wnt/β-catenin
transcriptional activity
- Decreases the mRNA
level of CCND1, CMYC,
MMP7, PLAU, XIN2,
NKD1, and DKK1
Lee et al. (2013)
2-
methoxycinnamalde
hyde
(2-MCA)
- 2-MCA inhibits the proliferation of
HCT116 colon cancer and MCF-7
breast cancer cells
- Not determined
Chew et al. (2010)
- 2-MCA inhibits tumor growth via
inhibition of angiogenesis in vivo
- 2-MCA inhibits the maturation of
tumor vasculature
- Inhibits the
phosphorylation of Tie2
Yamakawa et al.
(2011)
Eugenol
- Eugenol showed a dose-dependent
selective cytotoxicity toward HeLa
cells in comparison to normal cells
- Eugenol exhibits synergist anti-
cancer effect with gemcitabine in
HeLa cells
- downregulation of Bcl-2,
COX-2, and IL-1β
Hussain et al. (2011)
- Eugenol exhibits cytotoxicity and
induces apoptosis in colon cancer
cells
- Depletes MMP
- Generates ROS
- Activates PARP, p53 and
caspase-3
Jaganathan et al.
(2011)
- Eugenol significantly reduces the
incidence of MNNG-induced gastric
tumours
- Suppresses of NFκB
activation
- Down-regulates NF-κB
target genes (cyclin D1,
Cyclin B, PCNA, and
Gadd45)
Manikandan et al.
(2011)
- Eugenol shows cytotoxicity in breast
cancer cells and less toxic in non-
neoplastic breast epithelial cells
- Inhibits the expression
of p65 NFκB, β-catenin,
cyclin D1, survivin, and
Al-Sharif et al. (2013)
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- Eugenol induces apoptosis in breast
cancer cells
- Eugenol inhibits tumor growth of
breast tumor in vivo
E2F1.
- Activates pro-apoptosis
protein: caspase-3,
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-apoptosis
The most well-known and traditional anti-
cancer drugs act as tumor cell growth suppressor
(anti-proliferative) and cell death-inducer (pro-
apoptosis). The activity of cinnamon bark and/or its
constituents as the anti-proliferative and pro-
apoptosis are presented below.
Cinnamon extract/essential oil
Aqueous extract of C. cassia (AEC) exhibits an
anti-proliferative effect in vitro and in vivo in
various models of cancer, such as melanoma,
cervical cancer, and colon cancer (Kwon et al.,
2009; Kwon et al., 2010; Koppikar et al., 2010).
Koppikar et al. (2010) found that AEC increases
intracellular levels of calcium, leads to perturbation
of mitochondrial membrane potential, which
ultimately induces apoptosis in SiHa cervical cancer
cells. Another study by Kwon et al. (2010) found
that AEC also suppresses the expression of anti-
apoptotic proteins (e.g. Bcl-2, BcL-xL, and survivin)
by down-regulating the activity and expression level
of NFκB and AP1 proteins.
Another species of cinnamon, C. burmannii,
also exhibits anti-cancer potency. Schoene et al.
(2005) reported that the aqueous extract of C.
burmannii (AEB) inhibits the proliferation of some
myeloid cell lines: Jurkat, Wurzburg, and U937
cells). AEB decreases the intracellular phosphatase
activity that later induces cell cycle arrest in G2/M
phase. In addition, the essential oil of C. burmannii
shows cytotoxicity and induces apoptosis in T47D
breast cancer cells (Anjarsari et al., 2013).
Interestingly, cinnamon bark shows selective
anti-proliferative effect towards cancerous cells
rather than normal (non-cancerous) cells. Lee et al.
(2006) reported that the extract of cinnamon inhibits
the proliferation of HT-29 colon cancer cells, but not
CCD-112CoN normal colon cells. A similar result
was reported by Kwon et al. (2010); AEC inhibits
tumor cell growth (in HeLa, Caco-2, EL4, and Clone
M3 cell lines) in vitro, but not in normal cells
(primary mouse lymphocyte). Moreover, Singh et al.
(2009) reported that the aqueous extract of C.
zeylanicum (AEZ) shows significant higher
cytotoxicity in cancer cells rather than in the normal
cells. This selectivity feature is very important for
the anti-cancer drugs that hopefully the drugs have
minimum side effect for the clinical therapy.
Cinnamaldehyde
Cinnamaldehyde exhibits anti-proliferative
activity in various cancer cells, including leukemia
melanoma, colon cancer, nasopharyngeal carcinoma,
breast cancer, and hepatoma in vitro (Ka et al., 2003;
Fang et al., 2004; Cabello et al., 2009; Chew et al.,
2010; Wondrak et al., 2010; Chuang et al., 2012;
Daker et al., 2013). Moreover, cinnamaldehyde also
suppresses tumor cell progression in vivo in the
mouse model of cancer (Cabello et al., 2009).
Suppression of cancer cell growth can be
attributed to the inhibition of cell division (cell
cycle) and/or induction of cell death.
Cinnamaldehyde induces G1 cell cycle arrest in
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melanoma cells (Cabello et al., 2009). However,
other studies found that cinnamaldehyde induces
G2/M arrest in Jurkat and U397 leukemia cells; as
well as HCT116 colon cancer cells (Fang et al.,
2004; Chew et al., 2010; Nagle et al., 2012). Nagle
et al. (2012) reported several molecular events by
which cinnamaldehyde induces G2/M arrest.
Cinnamaldehyde down-regulates protein Cdk1 and
cdc25, which are the important proteins for G2/M
progression. Cyclin B, an important protein that
should be diminished during G2/M progression, was
sustained by cinnamaldehyde. Moreover,
cinnamaldehyde induces tubulin aggregation; hence
the cells in G2/M phase can not further divide
themselves.
In addition to the induction of cell cycle arrest,
cinnamaldehyde induces apoptosis in leukemia,
colon cancer, breast cancer, hepatoma, and human
nasopharyngeal carcinoma (NPC) cells (Ka et al.,
2003; Zhang et al., 2010; Chew et al., 2010; Chuang
et al., 2012; Daker et al., 2013). Several mechanisms
contribute to the apoptosis effect of cinnamaldehyde,
such as generation of intracellular ROS (Ka et al.,
2003), up-regulation of cell death surface
receptor Fas (Zhang et al., 2010), and modulation of
pro- and anti-apoptosis proteins (Chuang et al.,
2012; Daker et al., 2013).
Cinnamic acid
Cinnamic acid exhibits cytotoxicity and
induces apoptosis in HT-144 human melanoma
cells (de Oliveira Niero and Machado-Santelli,
2013). Cinnamic acid up-regulates the activity of
caspase-3 and expression of Bax, the pro-apoptotic
proteins; while decreasing the expression of Bcl-2,
an anti-apoptotic protein (de Oliveira Niero and
Machado-Santelli, 2013). Interestingly, cinnamic
acid also exhibits anti-cancer activity in the cancer
stem cells. Huang et al. (2012) examined the effect
of cinnamic acid in lung cancer stem cells.
Cinnamic acid inhibits the proliferation as well as
induces apoptosis and G1 arrest in the lung cancer
stem cells.
2-hydroxycinnamaldehyde (2-HCA)
2- HCA shows the anti-proliferative activity
in colon cancer and oral cancer; as well as induces
apoptosis in those cells (Hong et al., 2007; Lee et
al., 2007; Kim et al., 2010). Lee et al. (2013) also
showed that 2-HCA inhibits tumor progression in
vivo. Hong et al. (2007) found that 2-
hydroxycinnamaldehyde decreases mitochondrial
membrane potential, resulting in cell apoptosis. Lee
et al. (2007) showed that 2-hydroxycinnamaldehyde
modulates the pro- and anti-apoptotic protein levels,
such as caspase-3 and Bcl-2. In addition to
apoptosis, 2-HCA induces cell cycle arrest in G2/M
phase (Kim et al., 2010). 2- HCA also inhibits the
transcriptional and DNA binding activity of AP-1, a
transcriptional factor important for cancer cell
growth (Lee et al., 2007).
2- HCA is the only constituent of cinnamon
bark that has been studied for its direct protein target
in cancer cells. Hong et al. (2007) performed a pull-
down assay and found that 5 subunits of proteasome
complex interacted physically with 2-
hydroxycinnamaldehyde. This interaction inhibits
the activity of proteasome, resulting in various
perturbations inside the cancer cells, leading to
apoptosis. Even though not yet elucidating the direct
binding site, Hong and colleague suggests that 2-
hydroxycinnamaldehyde is an effective proteasome
inhibitor by inactivating multiple catalytic activities
of proteasome. Another possible target of 2-HCA is
the Wnt/β-catenin pathway. Lee et al. (2013) showed
that 2-HCA inhibits the transcriptional activity of
Wnt/β-catenin. This inhibition results in down-
regulation of various gene targets of Wnt/β-catenin
signaling, such as CCND1, CMYC, MMP7, PLAU,
XIN2, NKD1, and DKK1, which are the proteins that
play role in cell proliferation, survival, and motility.
2-methoxycinnamaldehyde (2-MCA)
2-MCA inhibits the proliferation of
HCT116 colon cancer cells (Chew et al., 2010).
However, further study is needed to elucidate its
exact molecular mechanism.
Eugenol
Although not only found in cinnamon bark,
eugenol is one of the major constituents of
cinnamon. An interesting feature of eugenol is that it
selectively toxic to cancer cells, but less toxic in
normal cells. Hussain et al. (2011) reported that
eugenol exhibits cytotoxicity in HeLa cervical
cancer cells, but not in normal cells. Another study
by Al-Sharif et al. (2013) showed that eugenol is
more toxic in the breast cancer cells rather than in
non-neoplastic breast epithelial cells. Eugenol
induces apoptosis in cervical cancer, colon cancer,
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and breast cancer cells in vitro (Hussain et al., 2011;
Jaganathan et al., 2011; Al-Sharif et al., 2013).
Eugenol also exhibits anti-tumor activity in vivo, in
rats developing MNNG-induced gastric tumors
(Manikandan et al., 2011) and breast cancer-
xenografted mice (Al-Sharif et al., 2013).
At the molecular level, eugenol activates the
pro-apoptotic proteins, such as PARP, caspase-3,
caspase-1, and caspase-9; as well as up-regulates cell
cycle regulator proteins p53 and p21 (Jaganathan et
al., 2011; Al-Sharif et al., 2013). Eugenol also
suppresses the expression and activation of NFκB,
resulting in down-regulation of NF-κB target genes
(cyclin D1, Cyclin B, PCNA, Gadd45) (Manikandan
et al., 2011).
Angiogenesis
To supply the nutrition and oxygen for their
growth, cancer cells form blood vessels in a process
called angiogenesis. Hypoxia, a condition in which
cancer cells lack of oxygen, plays a key role in
angiogenesis; which then activates VEGF signaling
as the important mediator of angiogenesis (Hanahan
and Weinberg, 2011). The activity of cinnamon bark
and/or its constituents as an anti-angiogenic agent is
discussed below.
Cinnamon extract/essential oil
Kwon et al. (2009) reported that AEC inhibits
tumor angiogenesis in vivo and down-regulates the
level of pro-angiogenic factors (e.g. EGF, VEGF-a,
TGF-b, and FGF). They also found that AEC
decreases the level of HIF-1α, a transcription factor
that is active in hypoxia condition and promote
tumor angiogenesis. Another study by Bansode et
al. (2013) reported that AEC inhibits the formation
of blood vessels in HUVEC cells and zebrafish
embryo. More over, Bansode et al. showed that
AEC inhibits the expression of PKC and inactivates
MAPK/Akt signaling, which turns out decreases the
expression of VEGFR.
2-methoxycinnamaldehyde (2-MCA)
Yamakawa et al. (2011) showed that 2-MCA
suppresses tumor growth in vivo by inhibiting
angiogenesis. Moreover, 2-MCA inhibits the
maturation of blood vessels in the tumor (tumor
vasculature). At the molecular level, 2-MCA inhibits
the phosphorylation of Tie2, a vascular growth
factor that is overexpressed in various tumors and
induces angiogenesis.
Metastasis
In the onset of cancer, cancer cells starts to
grow in the certain part of the body and become
much more harmful once they spread to the other
parts of the body, in a process called metastasis
(Hanahan and Weinberg, 2011). The metastasis
process consists of two steps: invasion and
migration. Matrix-metalloproteinase protein (MMP)
family mediates these processes by degrading the
extracellular matrix (ECM) proteins of the cells,
make it possible for cancer cells to sneak out their
original place and migrate to other parts of the body
(Deryugina and Quigley, 2006). The activity of
cinnamon bark and/or its constituents as an anti-
metastatic agent is presented below.
Cinnamon extract/essential oil
Koppikar et al. (2010) found that AEC
decreases the expression of MMP-2, both the mRNA
and protein level, in SiHa cervical cancer cells.
Furthermore, AEC also down-regulates the level of
HER-2 protein, an important marker in cervical
cancer related to the invasion capacity of the tumor
cells.
Cinnamic acid
Yen et al. (2011) and Tsai et al. (2013)
reported that cinnamic acid inhibits the invasive
ability of A549 lung adenocarcinoma cells.
Cinnamic acid decreases the mRNA level and
activity of MMP-2 and MMP-9, as well as
suppresses the activity of NFκB and AP-1 (Tsai et
al., 2013). Moreover, cinnamic acid also reduces the
invasive ability of lung cancer stem cells (Huang et
al., 2013). Interestingly, the cis form of cinnamic
acid exhibits a better anti-metastatic activity
compared to the trans-cinnamic acid (Yen et al.,
2011).
2-hydroxycinnamaldehyde (2-HCA)
Ismail et al. (2013) reported the potency of 2-
HCA as an anti-metastatic agent. They showed that
sub-toxic dose of 2-HCA inhibits breast cancer cell
migration in vitro. 2-HCA also inhibits epidermal
growth factor (EGF)-induced epithelial-
mesenchymal transition (EMT) in breast cancer
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cells. In vivo, 2-HCA is able to inhibit lung
metastasis and suppress micro-metastasis.
At the molecular level, 2-HCA suppresses the
protein level of Snail, a transcriptional repressor of
E-cadherin. Therefore, the transcription of E-
cadherin, a protein important protein for cell-cell
adhesion, is increased; resulting in the stronger cell-
cell integrity. Moreover, 2-HCA induces KLF17
expression. KLF17 is a repressor of Id-1, a protein
that increases the invasion of breast cancer cells.
Consequently, the 2-HCA decreases the expression
of Id-1 and inhibits breast cancer invasion.
Tumor-promoted inflammation
It was thought that the immune cells found in
the cancerous tissues aim to eradicate cancer cells
inside the tissue. It turns out that those immune cells
promote inflammation within the tumor. That
inflammation then provides the tumor
microenvironment with various bioactive molecules,
including growth factors and pro-angiogenic factors
(Hanahan and Weinberg, 2011). Inflammation also
plays an important role in tumor initiation.
Therefore, an anti-inflammatory agent has the
potency to be developed as an anti-cancer and
chemopreventive agent. The activity of cinnamon
bark and/or its constituents as an anti-inflammatory
agent is discussed below.
Cinnamon extract/essential oil
Kwon et al. (2010) reported that AEC
down-regulates the activity of NFκB, an important
protein for inflammation. In addition, Lee et al.
(2006) reported that the ethanol extract of cinnamon
decreases the production of PGE2 and the expression
of COX-2, two important mediators of
inflammation.
Cinnamaldehyde
Several studies showed the anti-inflammatory
activity of cinnamaldehyde in models other than
cancer cells. Kim et al. (2007) showed that
cinnamaldehyde inhibits the activation of NFκB via
three signal transduction pathways: NIK/IKK, ERK,
and p38 MAPK. Cinnamaldehyde also blocks IL-1β-
induced PGE2 production in the mouse cerebral
microvascular endothelial cell (Ma et al., 2008) and
mouse macrophage RAW264.7 cells (Zhang et al.,
2012). Zhang et al. also reported that
cinnamaldehyde suppresses the expression of PGE-
synthase-1 (mPGES-1), an important inducer of
PGE2 production.
Immunomodulation
The immune system is very important for
cancer elimination as it can help to fight cancer cells
with no toxicity to normal tissue. However, the
problem arises as the eternal mutation in cancer cells
gives them the ability to evade the immune system.
Therefore, scientists develop some strategies to
utilize the components of immune system as cancer
therapy, such as by directly targeting specific
antigens expressed by cancer cells or targeting the
immune system in the tumor microenvironment,
such as cytokines, suppressors of Treg or MDSC
activity, or antibodies that modulate T-cell activity
(Finn et al., 2012).
Cinnamon extract is able to modulate the
activity of T cells, the cytotoxic immune cells. AEC
increases the increased the anti-tumor activities of
CD8+ T cells in tumor draining-lymph nodes (Kwon
et al., 2009). Kwon and colleagues found that AEC
increases the cytolytic molecules (IFN-ϒ and TNF-
α) expressed in the surface of CD8+ T cells.
Furthermore, AEC increases the killing activity of
CD8+ T cells toward cancer cells.
Redox homeostasis in cancer cells
Redox homeostasis plays an important yet
complex role in the normal and cancer cells. The
main component of redox homeostasis is the reactive
oxygen species (ROS), which at the low level serves
as a mediator of signal transduction; while at the
high level disrupts various cell components, leading
to excessive mutations and/or cell death (Sosa et al.,
2013). Therefore, the level of intracellular ROS must
be regulated through a reliable redox system, which
comprises of various enzymatic systems, such as
glutathione redox system, thioredoxin system, and
Nrf2/Keap1-ARE pathway (Wondrak et al., 2009).
Cinnamaldehyde
Ka et al. (2003) reported that
cinnamaldehyde increases intracellular in HL60 pro-
myelocytic leukemia cells. Another study by Cabello
et al. (2009) also showed that cinnamaldehyde
increases the intracelullar reactive oxygen species
(ROS) that leads to cancer cell death. However, at
the sub-toxic dose, cinnamaldehyde up-regulates the
oxidative stress response genes such as heme
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oxygenase-1 (HMOX1), sulfiredoxin 1 homolog
(SRXN1), thioredoxin reductase 1 (TXNRD1).
Moreover, Wondrak et al. (2010) also reported a
similar result. Wondrak and colleagues found that
cinnamaldehyde is a potent activator of Nrf2
transciption. Sub-toxic concentration of
cinnamaldehyde (concentration range 6–10 μM)
strongly induced the transcription of Nrf2.
Cinnamic acid
Patra et al. (2012) showed the activity of
cinnamic acid as an antioxidant. Cinnamic acid
increases the activity of antioxidant enzymes, such
as superoxide dismutase, catalase and glutathione-S-
transferase, as well as reduces lipid peroxidation.
2-hydroxycinnamaldehyde (2-HCA)
Chew et al. (2010) reported that 2-HCA
inhibits thioredoxin reductase enzymatic activity.
Eugenol
Jaganathan et al. (2011) reported that eugenol
treatment elevates the intracellular ROS levels after
12 h and sustained until 48 h. Pre-treatment of
cancer cells with n-acetyl-cysteine (NAC), a
powerful antioxidant, blocked eugenol-induced
apoptosis. This result suggests that ROS is a key
player in eugenol activity as an anti-cancer agent.
Co-chemotherapy
Combination chemotherapy (co-
chemotherapy) is a strategy to increase the
effectiveness of anti-cancer therapy by combining
two or more anti-cancer agents. In addition, co-
chemotherapy also aims to reduce the side effects of
a strong anti-cancer drug.
Cinnamon extract/essential oil
Anjarsari et al. (2013) found that the essential
oil of C. burmannii (EOB) exhibits synergistic
cytotoxic effect with doxorubicin in T47D breast
cancer cells. This essential oil of EOB also performs
synergist effect with cisplatin to induce cell cycle
arrest and apoptosis in HeLa cells (Larasati et al.,
2014). This synergist activity is expected to lower
the dose of doxorubicin in cancer clinical therapy.
Cinnamaldehyde
Daker et al. (2013) reported that
cinnamaldehyde exhibits higher cytotoxicity than
cisplatin in C666-1 human nasopharyngeal
carcinoma (NPC) cells. However, cinnamaldehyde
also shows a synergist anti-cancer effect when
combined with cisplatin. Interestingly,
cinnamaldehyde also exhibits synergist cytotoxicity
with cytokine-induced killer (CIK) cells toward
K562 leukemia cells (Zhang et al., 2010). The CIK
cells resemble bone marrow transplantation that is
usually performed in leukemia patients. Therefore,
Zhang et al. suggest that cinnamaldehyde is
compatible to be used even in the leukemia patient
with former bone marrow transplantation.
Cinnamic acid
Patra et al. (2012) reported that cinnamic acid
pre-treatment protects bone marrow and hepatic cells
from cyclophosphamide-induced oxidative stress.
This activity of cinnamic acid occurs as it induces
the activity of antioxidant enzymes, such as
superoxide dismutase, catalase, and glutathione-S-
transferase in the liver and bone marrow of mice,
which counter the oxidative stress caused by
cyclophosphamide.
FUTURE PROSPECT AND STRATEGY
After a thorough literature study, we found
that the cinnamon and its constituents exhibit anti-
cancer activities through various mechanisms,
including anti-proliferation, pro-apoptosis, anti-
angiogenesis, anti-metastasis, inhibition of tumor-
induced inflammatory, immunomodulation,
modulation of redox homeostasis, and combination
chemotherapy. Astonishingly, despite its extensive
anti-cancer mechanism, cinnamon selectively toxic
to the cancer cells rather than normal cells (Lee et
al., 2006; Kwon et al., 2010; Singh et al., 2009);
which is an important feature for the development of
anti-cancer agents with less side effect. However, in
spite of the diverse molecular anti-cancer
mechanisms of cinnamon constituents have been
reported, only 2-hydroxycinnamaldehyde was shown
to have direct protein target(s) by Hong et al. (2007).
In this time of molecular targeted therapy, we need
to elucidate more the direct target(s) of cinnamon
constituents by using advanced biomedical and
medicinal chemistry approach in order to pinpoint
the exact anti-cancer mechanism of those
compounds.
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It is also interesting to note that compounds in
the cinnamon exhibit the different effect on the cell
redox homeostasis. Eugenol and 2-
hydroxycinnamaldehyde were reported to act as pro-
oxidant agents that increase the level of intracellular
ROS and inhibit the cellular antioxidant enzymes
(Chew et al., 2010; Jaganathan et al., 2011).
Cinnamic acid was reported as an antioxidant agent
(Patra et al., 2012); while cinnamaldehyde was
reported to promote the generation of intracellular
ROS, but also induce the activation of Nrf2 pathway
(Ka et al., 2003; Cabello et al., 2009; Wondrak et
al., 2010). An important factor to be noticed is the
dose used in those studies. Wondrak et al. (2010)
used a relatively low dose of cinnamaldehyde (6–10
μM) to induce the activation of Nrf2, which
practically did not show the toxic effect to the cancer
cells. On the other hand, Ka et al. (2003) found that
the IC50 value of cinnamaldehyde in HL60 cells is
30.7 μM; while Cabello et al. (2009) showed that
cinnamaldehyde 25 μM exhibits cytotoxicity in the
melanoma cells of >90%. These findings suggest
that cinnamaldehyde exhibits bi-phasic activity in
redox homeostasis of the cells: at low dose,
cinnamaldehyde triggers the activation of oxidative
stress response system, such as Nrf2; while at the
high dose, cinnamaldehyde boosts the intracellular
ROS level as one of its anti-cancer mechanism.
Whether cinnamon and its constituents
possess the anti- or pro-oxidant activities is
important to be acknowledged with care. There are
developing evidence showed that antioxidant favors
tumor growth. One of the important examples is
Nrf2 pathway, the major arranger for various
enzymes that protect the cells from oxidative stress
(Kansanen et al., 2013). While conventional studies
believe that Nrf2 pathway is important to protect the
normal cells from being cancerous; current
developing studies reported that Nrf2 might play an
important role in cancer chemoresistance and
enhancing cancer cell growth (Shibata et al., 2008;
Homma et al., 2009). As reviewed by Kansanen et
al. (2013), the Nrf2 activators are suitable to be used
as in cancer prevention; while the Nrf2 inhibitors are
suitable to be used in cancer therapy. Therefore, the
low dose cinnamaldehyde is appropriate to be used
in cancer prevention; while the higher dose is needed
for its use as the anti-cancer therapy. Considering
this topic, the cinnamon extract, which contains
various substances in moderate dosage, is more
suitable to be used as a chemopreventive agent.
Meanwhile, the pure chemical constituents of
cinnamon; such as cinnamaldehyde, cinnamic acid,
2-hydroxycinnamaldehyde, 2-
methoxycinnamaldehyde (2-MCA), and eugenol, are
potential to be developed as the anti-cancer agents
CONCLUSION
Altogether, cinnamon and its constituent
demonstrate potency to be used as the anti-cancer
and chemopreventive agents. Nevertheless, further
study needs to be conducted to determine the exact
molecular target(s) of cinnamon constituents.
Finally, a meta-analysis review with more data and
statistical analysis would help to reveal the potency
of cinnamon to the greater extent.
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