Content uploaded by Ivana Vrhovac Madunic
All content in this area was uploaded by Ivana Vrhovac Madunic on Nov 05, 2017
Content may be subject to copyright.
Cancer Letters xxx (2017) xxx-xxx
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com
Apigenin: A dietary flavonoid with diverse anticancer properties
Josip Madunića, 1, Ivana Vrhovac Madunićb, 1, Goran Gajskic, Jelena Popićd, Vera Garaj Vrhovacc, ∗
aDivision of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000, Zagreb, Croatia
bMolecular Toxicology Unit, Institute for Medical Research and Occupational Health, Ksaverska Cesta 2, 10000, Zagreb, Croatia
cMutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska Cesta 2, 10000, Zagreb, Croatia
dDepartment of Diagnostic and Interventional Radiology, Clinical Hospital Merkur, Zajčeva 19, 10000, Zagreb, Croatia
Received 9 August 2017
Received in revised form 25 October 2017
Accepted 26 October 2017
Available online xxx
Cell cycle arrest
Apigenin is a natural flavonoid found in several dietary plant foods such as vegetables and fruits. A large
number of studies conducted over the past years have shown that this particular natural compound has poten-
tial antioxidant, anti-inflammatory, and anticancer properties. Therefore, apigenin has generated a great deal
of interest as a possible chemotherapeutic modality due to its low intrinsic toxicity and remarkable effects on
normal versus cancerous cells, compared with other structurally related flavonoids. Here, we review its role
in anticancer research, as well as several cancer signalling pathways, including MAPK, PI3K/Akt and NF-κB
pathways, and their specific role in different cancer types. Based on the available literature, the beneficial ef-
fects of apigenin as a future anticancer modality are promising but they require further in vitro and in vivo
studies to enable its translation from bench to bedside.
Cancer is nowadays one of the most serious life-threating diseases,
affecting people of all ages and is considered one of the leading causes
of mortality and morbidity worldwide. Statistics show it is the second
most common cause of death after cardiovascular diseases in devel-
oped countries . Cancer cells are characterized by mutations and
genetic instabilities which consequently lead to impaired regulation
of cell cycle, uncontrolled proliferation and overcoming of apoptosis
and similar checkpoint mechanisms . Anticancer treatments usually
use compounds that target fast-dividing cells. This approach, regret-
tably, has a negative side effect because normal, fast-dividing cells
such as hair follicles and epithelial cells in the digestive system are
also affected. Furthermore, one of the aggravating circumstances is
that many cancer cells gradually develop resistance to conventional
forms of therapy . Therefore, many studies in the last few years
have focused on the development of an effective anticancer therapy
which would have little or no effect on normal cells.
In this regard, natural compounds from plants are proving to be
suitable candidates for such a therapy . Interfering with the process
of carcinogenesis through diet or by the added digestion of natural
compounds has been termed “chemoprevention” . An increasing
importance is being given today to alternative medicine and dietary
approach in prevention and treatment of cancer. A large number of
Email address: firstname.lastname@example.org (V. Garaj Vrhovac)
1These authors contributed equally to this work.
epidemiological, in vitro,in vivo and clinical studies demonstrated
growing evidence linking increased consumption of a plant-based diet
with a reduced risk of chronic diseases such as cancer, as well as
neurodegenerative, metabolic and heart diseases [6–11]. It should be
noted that many epidemiological studies reported inconsistent results.
This can be partly explained by the fact that those studies are based
on food questionnaires, which are not always an exact source of in-
formation. Furthermore, within an abundant number of plant species,
only 10% of them have been analysed as pharmacology agents. There-
fore, both in vitro and in vivo research present a better way to elucidate
the beneficial effect of plant phytochemicals. Accordingly, many re-
searchers have dedicated their studies to analyse a possible anticancer
effect of natural compounds from vegetables and fruits.
There are many categories of plant bioactive compounds, such as
alkaloids, glycosides, polyphenols, tannins, gums, resins and oils, and
many of these phytochemicals have been shown to possess low intrin-
sic toxicity and exert prominent effects on cancerous versus normal
cells. An encouraging fact is that, in the last few decades, nearly 70%
of all anticancer drugs originated from natural sources or are deriva-
tives of natural products .
The most extensively studied group of plant secondary metabo-
lites are polyphenols, characterized by their structure of multiple phe-
nol (benzene) rings . Polyphenols, ranging in their structure from
small molecules to highly complex compounds, are widely distrib-
uted in various vegetables, fruits, legumes, coffee, wine, beer, spices
and nuts [4,10]. Polyphenols are further divided into flavonoids, phe-
nolic acids, stilbenes, lignans and other polyphenols. Their structural
variance is the reason why polyphenols possess many different bio
2 Cancer Letters xxx (2017) xxx-xxx
logical functions; most importantly anticancer activity. This activity is
dependent on their structure, concentration and the type of cancer.
Flavonoids, a group representing 60% of all natural polyphenols,
are present in all parts of plants, especially in flowers and leaves.
Based on their structure, flavonoids can be classified into distinct
sub-groups including anthoxanthins (flavones and flavonols), fla-
vanones, flavanols, isoflavonoids and anthocyanidins. They exert their
anticancer activity through the induction of apoptosis in cancer cells.
Studies have shown that high dietary intake of flavonoids is associated
with reduced occurrence of many types of cancer [12,13], but there
is still insufficient data on the precise mechanisms of flavonoid anti-
cancer effects. Apart from the anticancer activity, flavonoid-mediated
health benefits include anti-oxidant activity through the removal of
free radicals, which are capable of damaging lipids, proteins and DNA
, anti-inflammatory, neuroprotective and antiproliferative activity,
as well as an ability to modulate signalling pathways involved in cen-
tral cell processes.
One of the most abundant and most studied flavonoid is 4′,5,7-tri-
hydroxyflavone, commonly referred to as apigenin, with molecular
structure C15H10O5and molecular mass 270.24 g mol−1 (Fig. 1). Api-
genin is found in significant quantities in a variety of vegetables and
fruits such as parsley, celery, chamomile, oranges, thyme, onions,
honey and spices, as well as beverages derived from plants; tea, beer
and wine [4,15]. The name “apigenin” comes from Apium genus in
Apiaceae family, a group of mostly aromatic flowering plants includ-
ing celery, carrot and parsley . It is a secondary plant metabolite,
usually found in nature in glycosylated form, more soluble than its
pure form which is unstable and quite insoluble in water and organic
solvents [9,15]. The first reference of apigenin in science literature
comes from the 1950s at what time Spicak and Subrt  analysed
its effect on histamine release. It was not until the 1980s that api-
genin was associated with the process of carcinogenesis when Birt et
al.  reported its effective anti-mutagenic and anti-promotion prop-
erties. Since then, apigenin has been investigated in many studies as
a potential cancer chemopreventive agent against a wide selection of
different cancer types.
Interest in apigenin, as a beneficial and health promoting agent, has
grown in recent years because of its low intrinsic toxicity and remark-
able effects on normal vs cancerous cells [18,19]. There is also very
little evidence that suggests that apigenin promotes adverse metabolic
reactions in vivo when consumed as part of a normal diet. Moreover,
apigenin has been increasingly recognized as a cancer chemopreven-
tive agent in a series of studies done both in vitro and in vivo. This
interest could be largely attributed to its potent antioxidant and anti-in-
flammatory activities . Indirect support to this hypothesis is pro-
vided by a study where consumption of flavonoid free diets by healthy
human volunteers has reportedly led to a decrease in the oxidative
stress markers such as antioxidant vitamins and superoxide dismutase
(SOD) activities, which are commonly associated with enhanced dis-
ease risk and progression .
A variety of biological effects of apigenin in a number of mam-
malian systems in vitro as well as in vivo are mainly related to its an
Fig. 1. . Chemical structure of dietary flavonoid apigenin.
tioxidant effects and its role in free radical scavenging. Besides, api-
genin exhibits anti-mutagenic, anti-inflammatory and antiviral effects
. The actions of apigenin in inhibiting the cell cycle, diminishing
oxidative stress, improving the efficacy of detoxification enzymes, in-
ducing apoptosis, and stimulating the immune system are also known
[21–23]. One human study demonstrated that apigenin was absorbed
systemically by a subject fed a diet rich in parsley. Results showed
that this subject had elevated levels of the antioxidant enzymes glu-
tathione reductase and SOD , while the activities of catalase and
glutathione peroxidase were found to be unchanged. Other biological
effects induced by flavonoids include the reduction of plasma levels
of low-density lipoproteins, inhibition of platelet aggregation, and re-
duction of cell proliferation [21–23,25]. This is also apparent from an-
other cross-sectional study conducted in Japan in which the total in-
take of flavonoids among women was found to be inversely correlated
with plasma total cholesterol and low-density lipoprotein concentra-
tion, after adjustment for age, body mass index, and total energy in-
take . Moreover, the effects of flavonoids on the hematologic sys-
tems were also performed in a 7-day study of 18 healthy men and
women examining the effects of a daily dietary supplement, providing
apigenin from parsley, on platelet aggregation and other haemostatic
variables. The authors of that study observed no significant changes
in collagen- or ADP-induced platelet number, factor VII, plasmino-
gen, and PAI-1 activity or fibrinogen concentrations . These spe-
cific properties categorise apigenin as part of a class of beneficial
compounds which possess health-promoting and disease-preventing
In the following chapters, including Tables and Figures, we pre-
sent a summary of apigenin anticancer activities including dose ranges
used in both in vitro and in vivo studies that exerted beneficial effects
against cancer growth and development.
2. Apigenin effects in cancers
2.1. Head and neck cancer
Several studies have evaluated the effect of apigenin on head and
neck cancers. Apigenin was shown to inhibit proliferation in human
head and neck squamous carcinoma cells which was followed with
G2/M cell cycle arrest and increase in intracellular reactive oxygen
species (ROS) levels. Growth inhibition was accompanied by apop-
tosis through the up-regulation of both tumour necrosis factor re-
ceptor (TNF-R) and TNF-related apoptosis-inducing ligand recep-
tor (TRAIL-R) signalling pathways . A study by Chakrabarti et
al.  investigated the synergistic effect of human telomerase re-
verse transcriptase (hTERT) knockdown and apigenin treatment in hu-
man malignant neuroblastoma cells. This combination therapy led to
cell proliferation with the inhibition of invasion and induced apop-
tosis characterized by down-regulation of MMP-2 and -9, N-Myc,
PCNA, CDK-2, CDK-4 and cyclin D1. In the next study, same au-
thors showed that combination of N-Myc knockdown and apigenin
exposure induced differentiation and apoptosis in SK-N-DZ and
SK-N-BE2 neuroblastoma cell lines which are known for N-Myc am-
plification. These effects were followed by a decrease in cell survival,
invasive potential and angiogenesis . Additional study by the same
group reported that the overexpression of tumour suppressor miR-138
enhanced the pro-apoptotic effects of apigenin in human neuroblas-
toma cells, through both intrinsic and extrinsic pathways of apopto-
sis . Furthermore, apigenin-mediated induction of apoptosis was
potentiated by the overexpression of Krüppel-like factor 4 (KLF4), a
zinc-finger transcription factor, in neuroblastoma cells .
Cancer Letters xxx (2017) xxx-xxx 3
Similarly, induction of apoptosis was also observed in api-
genin-treated FRO anaplastic thyroid carcinoma (ATC) cells. Treat-
ment with apigenin prompted apoptosis through the increase in c-Myc
expression followed by the phosphorylation of p53 and p38 . Fur-
ther research revealed that the treatment with PLX4032, an inhibitor
of mutated B-Raf kinase, increased the apigenin cytotoxic effect in
ATC cells which was further potentiated with subsequent Akt inhibi-
tion . Recently, same authors evaluated the effect of apigenin in
combination with TRAIL on survival of ATC cells . Combination
therapy reduced cell viability via modulation of the Bcl2/Bax ratio and
the suppression of Akt augmented the observed synergistic anticancer
effect of apigenin in ATC cells. Apoptosis in human papillary thy-
roid carcinoma (PTC) cells exposed to apigenin was associated with
ROS production, induction of DNA damage and G2/M cell cycle ar-
rest, which led to autophagy as witnessed by LC3-II accumulation in
treated cells .
Similar anticancer effects were observed in oral squamous cell car-
cinoma cells. Treatment with apigenin inhibited cell growth and in-
duced apoptosis accompanied by cell cycle arrest at both G0/G1 and
G2/M checkpoints. Therefore, authors suggested apigenin could be
used as an effective cell cycle regulating agent in cells with deregu-
lated, but still active cell cycle . In other study, administration of
apigenin and another flavonoid, hydroxygenkwanin (HGK), has been
shown to exert antiproliferative effects in C6 rat glioma cells. Api-
genin strongly sensitized glioma cells to apoptotic activity of HGK
through processes associated with Akt activation and suppression of
SOD activity . A study using the same model cells confirmed
the apigenin's anticancer potential, which was mediated via growth-
and migration inhibition through both apoptosis and autophagy. In-
duction of differentiation and a decrease in the expression of immune
response factors was observed in rat glioma cells after apigenin treat-
ment . Another study, which aimed to investigate the effect of api-
genin on glioma cells, demonstrated that apigenin inhibited cell via-
bility through apoptosis induction in U87 human glioma cells .
Apoptosis was followed by an increased miR-16 expression and sup-
pression of Bcl2 and NF-κB pathway.
Various studies have established that glucose transporter-1
(GLUT-1) is associated with chemoresistance in cancers and is con-
sidered to be an important marker of hypoxia in malignant tumours.
Study by Xu et al.  reported that apigenin treatment inhibits
GLUT-1 expression and by doing so sensitizes laryngeal carcinoma
Hep-2 cells to cisplatin chemotherapy. An in vivo study by the same
group showed that apigenin enhanced radiosensitivity of laryngeal
carcinoma and suppressed xenograft tumour growth through GLUT-1
and PI3K/Akt inhibition . Another recent study demonstrated api-
genin's cytotoxic effects in human oesophageal cancer cells. These ef-
fects were related to enhanced membrane permeability and induced
leakage of lactate dehydrogenase (LDH), which caused membrane
toxicity and led to apoptosis in apigenin-treated cells .
Moreover, Kim et al.  investigated possible therapeutic effects
of apigenin in treating CSC-like phenotypes in human glioblastoma
cells and found that apigenin markedly decreased cell viability, neu-
rosphere formation and invasiveness in glioblastoma stem-like cells.
Furthermore, apigenin inhibited the c-Met receptor tyrosine kinase
signalling pathway and suppressed the expression of stem-like mark-
ers CD133, Nanog, and Sox2. Similarly, it was also shown recently
that apigenin exposure significantly suppressed hypoxia-induced ex-
pression of CSC markers CD105, CD44, Nanog and VEGF in head
and neck squamous cell carcinoma cells. This effect was accompanied
by the apigenin-induced decrease of CSC marker-expressing cells in
overall population .
2.2. Breast cancer
Apigenin has been shown to block the progression and devel-
opment of progestin-dependent BT-474 breast cancer cell (BCC)
xenograft tumours in nude mice through apoptosis induction and de-
clined HER2/neu expression . This was accompanied by the api-
genin-mediated down-regulation of VEGF expression. A later study
evaluated the effect of apigenin exposure in HER2-transfected MCF-7
(ER-positive) BCC. Results have shown that apigenin inhibits cell
growth by promoting extrinsic apoptotic pathway, induces p53 and
p21 expression and suppresses STAT3 and NFκB signalling .
The same group demonstrated that apigenin exposure led to p53-de-
pendent apoptosis in MDA MB-453 , SKBR3  and BT-474
 BCC lines. The observed cell growth inhibition was associated
with caspase-dependent extrinsic pathway of apoptosis and suppres-
sion of STAT3/VEGF signalling pathway in these HER2-overexpress-
A study by Cao et al.  evaluated the crosstalk of autophagy
and apoptosis in apigenin-treated BCC. Autophagy was induced si-
multaneously with apoptosis in T47D and MDA MB-231 BCC af-
ter apigenin treatment, which was confirmed by increased levels of
LC3-II. Furthermore, subsequent inhibition of autophagy potentiated
the apigenin-induced apoptosis. Unlike most other studies, Harrison
et al.  concentrated their research on a low-dose apigenin effect
in BCC. Their results showed that sub-cytotoxic concentration of api-
genin blocked DNA synthesis, elevated ROS levels and repressed pro-
liferation in a panel of BCC lines, which authors attributed to Akt
inhibition. Furthermore, apigenin has exhibited cytotoxic effects in
MCF-7 BCC, which was accompanied by morphology changes, re-
duced motility and decreased intracellular communication in treated
cells due to a disturbed structure and decreased amount of intracellular
A study conducted in order to elucidate the effect of apigenin on
ER + MCF-7 and ER− SKBR3 BCC revealed that there were no sig-
nificant differences between the response of these two BCC lines to
apigenin treatment and concluded that the apigenin's antiproliferative
effect did not depend on the steroid hormone receptor status in BCC
It was shown recently that apigenin treatment blocked the ex-
pression of cytokine-activated programmed death-ligand 1 (PD-L1),
which enabled a T cell-mediated anticancer activity in BCC . The
detected immune-modulating effect of apigenin was followed by G2/
M cell cycle arrest and apoptosis. Interestingly, studies have shown
that apigenin is capable of antiproliferative activity in BCC through
epigenetic regulation. The findings by Tseng et al.  demonstrated
that apigenin increased p21 expression via H3 acetylation induction
and histone deacetylase (HDAC) inhibition, which led to cell cycle ar-
rest in G2/M phase in MDA MB-231 BCC.
2.3. Prostate cancer
Prostate cancer is one of the most prevalent cancers diagnosed in
men and the second leading cause of male cancer-related death af-
ter lung cancer. The abnormal changes in the insulin-like growth fac-
tor (IGF) axis are one of the markers of prostate cancer development,
progression and metastasis. In a review by Babcook and Gupta ,
the authors reported that apigenin was capable of modulating the IGF
axis and its signalling in prostate cancer cells (PCC). Oral consump-
tion of apigenin decreased prostate cancer levels of IGF-1 and inhib-
ited downstream signalling followed by cell cycle arrest, growth inhi-
bition and apoptosis in PCC. Furthermore, the same group indicated
4 Cancer Letters xxx (2017) xxx-xxx
that apigenin administration to TRAMP (transgenic adenocarcinoma
of the mouse prostate) mice (strain which spontaneously develops
prostatic adenocarcinoma) supressed prostate carcinogenesis by
down-regulating IGF-I/IGFBP-3 signalling. This was accompanied
with reduced angiogenesis and metastasis due to the inhibition of
VEGF, uPA, MMP-2, and MMP-9 expression. This study was de-
signed to be comparable with consumption in humans so each mouse
was treated with 20 and 50 μg/day apigenin over a period of 20 weeks
Another study described the apigenin-mediated growth inhibitory
activity in PCC, caused by the inhibition of class I histone deacety-
lases (HDACs) . Apigenin treatment induced cell cycle arrest fol-
lowed by apoptosis in PC-3 and 22Rv1 prostate cancer cell lines,
which was further confirmed when the authors used an in vivo model
of athymic nude mice with prostate cancer xenografts. Furthermore,
apigenin was shown to bind and inhibit adenine nucleotide translo-
case-2, an important transporter in the inner mitochondrial membrane,
which up-regulated the death receptor 5 (DR5) and consequently in-
duced tumour necrosis factor-related apoptosis in LNCaP and DU145
human prostate cancer cell lines .
A study by Shukla et al.  showed that apigenin supressed the
activity of the inhibitor of apoptosis (IAP) proteins, which was ac-
companied by a decrease in Bcl-xL and Bcl- 2 and an increase in
the active form of Bax protein. This triggered apoptosis in PC-3 and
DU145 PCC. The same research group also reported that apigenin
suppressed prostate cancer progression by targeting the PI3K/Akt/
FoxO-signalling pathway . Apigenin treatment activated the Fox-
O3a transcription factor and induced the expression of its downstream
targets; BIM and p27, which led to cell cycle arrest and reduced via-
bility in prostate tumours. Further studies by the same authors demon-
strated apigenin's ability to bind and suppress IKKα thereby inhibit-
ing NF-ĸB activation. This was followed by a decreased cell prolifera-
tion and invasiveness of PCC . Apigenin treatment also down-reg-
ulated the expression of NF-κB-regulated genes involved in prolifer-
ation (cyclin D1 and COX-2), anti-apoptosis (Bcl-2 and Bcl-xL) and
angiogenesis (VEGF) .
Development of metastases is the main reason behind prostate can-
cer-associated mortality because primary site disease is organ-con-
fined and rather treatable nowadays. An important factor in prostate
tissue angiogenesis is the vascular endothelial growth factor (VEGF).
Apigenin was shown to inhibit the TGF-β-induced VEGF production
in human PCC and consequently was able to supress prostate carcino-
genesis by modulating the Smad2/3 and Src/Fak/Akt pathways .
Similarly, a study by Zhu et al.  also recognized the importance
of decreasing the rate of metastasis in prostate cancer treatment. They
demonstrated the apigenin-mediated inhibition of migration and inva-
sion of DU145 PCC through the reversal of epithelial to mesenchymal
transition (EMT) followed by G2/M cell cycle arrest and apoptosis.
Another study revealed that apigenin selectively inhibited protea-
somal degradation of estrogen receptor-β (ER-β), an important tu-
mour suppressor in prostate cancer, through precise inhibition of chy-
motrypsin-like activity of proteasome. This resulted in PCC apoptosis
. One of the mechanisms behind apigenin's chemopreventive ac-
tivity in prostate cancers could be the inhibition of androgen hormone
production as was suggested by Wang et al. . Apigenin was able
to inhibit steroidogenic enzymes by competing with the binding sites
and acting as steroid substrate.
Cancer stem cells (CSCs) are involved in metastasis, relapse of
cancers and drug resistance in various cancer types. Treatment with
apigenin was shown to inhibit the survival of prostate CSC through
an extrinsic apoptotic pathway . Apigenin-treated prostate CSC
sustained cell cycle arrest and a decrease in migration caused by par-
tial down-regulation of PI3K/Akt and NF-κB signalling. The same re-
search group analysed the effect of combined therapy by cisplatin and
apigenin on prostate CSC growth and migration and found that api-
genin significantly increased cisplatin cytotoxic and anti-migration ac-
tivity in prostate CSC .
2.4. Colorectal cancer
Colorectal cancer (CRC) is a type of cancer which affects men and
women equally. Even though most colorectal tumours can be surgi-
cally treated, recurring metastases are the reason for high CRC-asso-
ciated mortality. This clearly emphasizes the need for effective treat-
ment of this disease. A study by Chunhua et al.  showed that
apigenin was capable of suppressing proliferation and migration in
several colorectal adenocarcinoma cell lines through the up-regula-
tion of an actin-binding protein and potential CRC suppressor, trans-
gelin, with a subsequent down-regulation of MMP-9. Additionally,
apigenin was observed to exert similar antiproliferative and anticancer
effects in CRC cell lines via inhibition of the Wnt/β-catenin signalling
pathway. Apigenin supressed β-catenin/TCF/LEF signalling activa-
tion and prevented the expression of Wnt target genes by blocking the
transport of β-catenin into the nucleus . Furthermore, it was shown
that apigenin improved the apoptotic activity of ABT-263, a BH3
mimetic inhibitor in colon cancer cells. Apigenin down-regulated the
expression of prosurvival protein Mcl-1 and inhibited Akt and ERK
signalling pathways, which synergistically enhanced ABT-263-in-
duced anticancer effects, both in cell and in vivo models . A recent
study by Wang and Zhao  found that apigenin induced apoptosis
in colon carcinoma cells equally through intrinsic mitochondrial and
extrinsic pathways, which was caused by the apigenin-mediated pro-
duction of ROS and induction of endoplasmic reticulum (ER) stress.
There are data in the literature describing apigenin being able to
induce both apoptosis and autophagy in colon cancer cells. Treatment
with apigenin inhibited growth of HCT116 cells through G2/M cell
cycle arrest and induced cell death, both by apoptosis and autophagy,
which authors attributed to apigenin's effect on PI3K/Akt/mTOR path-
way . Interestingly, Banerjee and Mandal  recently reported
that while high concentrations of apigenin in shorter treatment caused
apoptosis, lower concentrations over longer period of treatment led to
oxidative stress and premature senescence in CRC cell lines HT-29
Recently, it was confirmed that apigenin acted as an inhibitor of
NEDD9, a scaffolding protein strongly associated with cancer metas-
tasis and development. Apigenin treatment decreased NEDD9 expres-
sion resulting in the suppression of CRC cell migration, invasion and
metastasis . Similar antiproliferative effects were observed in gas-
tric cancer cells where apigenin induced apoptosis through the in-
crease of Bax/Bcl-2 expression ratio, this was followed by a decrease
in the mitochondrial membrane potential and activation of caspase-3
cascade. At the same time, apigenin showed no substantial effects on
proliferation and apoptosis of normal gastric cells .
Using an azoxymethane (AOM)-induced intestinal adenocarci-
noma in Wistar rat model, Tatsuta et al.  found that apigenin
decreased the incidence of lymphatic vessel invasion of adenocarci-
nomas and together with in vitro results showed that apigenin su-
pressed cancer metastasis by inhibiting phosphorylation of MAPK.
The formation of colon aberrant crypt foci (ACF) and high activity
of ornithine decarboxylase (ODC) are considered to be the prognostic
markers of colon cancer. A study by Au et al.  reported that di-
etary apigenin reduced the formation of ACF and decreased ODC ac
Cancer Letters xxx (2017) xxx-xxx 5
tivity in AOM-induced CF-1 mice model. Furthermore, ODC activ-
ity was significantly inhibited by 10 and 30 μM apigenin in Caco-2
CRC cells. The authors also evaluated colon tumorigenesis using Min
mice, a strain with mutant APC gene, predisposed to intestinal ade-
noma formation. Contrary to the two AOM-injected mice studies,
dietary apigenin did not supress adenoma formation in Min mice.
Similarly, it has been shown that dietary apigenin reduced the inci-
dence of high multiplicity aberrant crypt foci (HMACF) in the colon
of Sprague-Dawley rats. Because HMACF are one of the earliest
pre-cancer changes seen in the colon, these results suggest that api-
genin may have a protective role against colon carcinogenesis. Fur-
thermore, expression of proinflammatory enzymes COX-2 and iNOS
was analyzed but the authors found that apigenin treatment had no ef-
fect on their expression in the aforementioned in vivo cancer model
An in vitro study by Zhong et al.  revealed that apigenin in-
duced apoptosis and significantly reduced proliferation of human CRC
cells HCT-116 through PKCδ and ATM kinase pathways, affecting
the expression of NAG-1, p53, and p21. Apigenin modulated the ex-
pression of p53 and p21 at the translational level whereas NAG-1 was
affected at the transcriptional level. As opposed to previous studies in
Min mice , the results of this study showed that apigenin inhibited
intestinal tumorigenesis with evident reduction in polyp number and
load. The differences between these two in vivo studies could be due
to dissimilar treatment parameters such as way of feeding, timing of
treatment, and dosage of apigenin. A recent study by Banerjee et al.
 described apigenin as a potential chemotherapeutic agent against
CRC, both in vitro and in vivo, and aimed to develop a lipid nanocar-
rier for more effective delivery of apigenin. Using athymic nude mice,
the authors demonstrated that administration of apigenin: 1) decreased
tumour volume in both apigenin and liposomal-apigenin treated an-
imals, being more significant with the carrier; 2) attenuated tumour
vasculature; and 3) inhibited cellular proliferation as witnessed by re-
duction of Ki-67. These in vivo results are of great importance because
they indicate future clinical potential of apigenin-based vesicles.
2.5. Pancreatic cancer
A study conducted in order to evaluate the effect of apigenin in
pancreatic cancer cells (PaCC) discovered that apigenin was able to
restore the activity of mutated p53 in MiaPaCa-2 and BxPC-3 PaCC
lines and by doing so, decrease proliferation and induce apoptosis in
those cells . Apigenin treatment also promoted the binding of p53
to DNA and up-regulated the expression of p21 and pro-apoptotic
PUMA. Using the same model cells, the authors showed that apigenin
supressed mutagen-induced β-adrenergic receptor (β-AR) signalling
and subsequent activation of its downstream targets; focal adhesion
kinase (FAK) and ERK kinase. As a result, apigenin exposure re-
duced the mutagen-enhanced proliferation and migration of β-AR-ex-
pressing PaCC . Furthermore, apigenin has been shown to effec-
tively potentiate the anticancer effect of chemotherapeutic drugs in
BxPC-3 PaCC. Such combination therapy was able to inhibit cell pro-
liferation where timing and concentration were shown to play a cru-
cial role; pretreatment with apigenin was more effective than the si-
multaneous application of apigenin and chemotherapeutic drug .
A later study by the same group demonstrated that apigenin treatment
in BxPC-3 and PANC-1 PaCC lines inhibited the GSK-3β/NF-κB
signalling pathway, which led to G2/M cell cycle arrest and acti-
vated the intrinsic pathway of apoptosis . Analysis of gene ex-
pression showed that growth inhibition could be related to the api-
genin-enhanced expression of inflammatory genes. Similarly, Wu et
al.  observed that apigenin exposure in PaCC led to suppres
sion of the IKK-β-mediated NF-κB activation. Apigenin blocked the
IKK-β activity, NF-κB DNA binding, induced apoptosis and reduced
the growth of pancreatic cancer xenografts in nude mice.
A recent study reported of an interesting activity of apigenin in
pancreatic cancer. Ikaros, a transcription factor important in lympho-
cyte development and anticancer immune response, is negatively reg-
ulated by casein kinase 2 (CK2). The findings of Nelson et al. 
showed that apigenin treatment caused specific CK2 inhibition, which
in turn stabilized Ikaros expression in pancreatic cancer. This was fur-
ther confirmed using an in vivo Panc02 mice model where apigenin
exposure facilitated survival, reduced tumour size and, overall, im-
proved the anticancer immune response in pancreatic cancer.
2.6. Skin cancer
Previous studies have evaluated the effect of apigenin in melanoma
cancer cells. Apigenin treatment elevated ROS production, depleted
glutathione (GSH) and SOD levels, which triggered apoptosis through
its intrinsic pathway in human A375 melanoma cells. Cells also under-
went apigenin-mediated alterations in mitochondrial functions char-
acterized mainly by oxidative phosphorylation impairment . Re-
cently, it was shown that A2058 and A375 melanoma cells exposed
to apigenin exhibited reduced cell migration and diminished FAK and
ERK 1/2 activity, which sensitized cells to anoikis; detachment-in-
duced apoptosis . A study by Chao et al.  demonstrated that
non-toxic doses of apigenin supressed VEGF expression in uveal
melanoma SP6.5 and C918 cell lines in a dose- and time-dependent
manner by inhibiting PI3K/Akt and ERK1/2 signalling.
Further studies have also evaluated the role of STAT3 signalling
on the apigenin anticancer activity in melanoma cells. Exposure of
murine melanoma B16F10 to apigenin resulted in metastasis, migra-
tion and invasion inhibition via down-regulated STAT3 signalling.
This was accompanied by apigenin-influenced suppression of STAT3
downstream targets: MMP-2, -9, VEGF and Twist1 . Interest-
ingly, a recent study using same model cells showed that natural de-
rivative of apigenin; apigenin-7-glucoside exerts antiproliferative and
differential activity in B16F10 melanoma cells. Treatment induced
apoptosis and significantly promoted melanin synthesis, as well as the
activity of tyrosinase, melanogenesis-related enzyme .
Study designed to assess the effect of apigenin on A375 and C8161
melanoma cell lines (different in their BRAF mutation status), re-
vealed that apigenin inhibited cell growth through G2/M cell cycle ar-
rest and induced apoptosis which was attributed to apigenin-mediated
inhibition of Akt/mTOR pathway . Moreover, it was observed that
apigenin exposure triggered changes in the dendrite morphology in
both cell lines which authors associated with glutamate signalling in-
An in vivo study by Kiraly et al.  suggested that apigenin may
inhibit skin cancer development by down-regulating COX-2. Api-
genin exposure of non-tumour epidermis in tumour bearing SKH-1
mice decreased the expression of COX-2, prostaglandin PGE2, recep-
tors EP1 and EP2, and increased terminal differentiation. Even though
apigenin failed to inhibit the COX-2 pathway or promote differen-
tiation in tumours, the apigenin-treated mice exhibited diminished
COX-2 in their epidermis and developed fewer tumours.
2.7. Liver cancer
As other studies have demonstrated, apigenin treatment in com-
bination with cytokine TRAIL is able to induce apoptosis with bet-
ter efficacy that either compound alone . A similar effect was ob
6 Cancer Letters xxx (2017) xxx-xxx
served in Huh-7 hepatocellular carcinoma cells (HCC), which were
simultaneously exposed to apigenin and TRAIL. Huh-7 cells, other-
wise resistant to TRAIL therapy, were sensitized by apigenin/TRAIL
treatment, which prompted the upregulation of Bax/Bcl-2 ratio and ac-
tivated caspase-dependent apoptosis . A later study by the same
group reported of the similar apigenin-mediated priming of HepG2
HCC to TRAIL-induced apoptosis. The authors showed that com-
bination therapy induced apoptosis by stimulating DR5 expression
through the ERK signalling pathway . Similarly, a study by Hu
et al.  revealed that apigenin potentiated the cytotoxic activity of
5-flurouracil (5-FU) in SK-Hep-1 and BEL-7402 HCC. Co-treatment
activated the mitochondrial apoptotic pathway via ROS accumula-
tion and mitochondrial membrane depolarization. The synergistic anti-
cancer effect of apigenin/5-FU was also observed in HCC xenografts.
Apigenin has been associated with epithelial-to-mesenchymal tran-
sition in HCC. Recent findings demonstrated that exposure of
Bel-7402 and PLC HCC to apigenin resulted in change of EMT
marker expression accompanied by the inhibition of NF-κB/Snail sig-
nalling. Apigenin also inhibited proliferation, invasion and migration
of HCC cells and reduced HCC xenografts growth, which suggests
that apigenin inhibits EMT through NF-κB/Snail suppression in HCC
. The use of apigenin as an efficient therapeutic drug in HCC
treatment was also confirmed in a recent study where selective toxi-
city of apigenin on cancerous versus non-cancerous hepatocytes was
evaluated. The results showed that apigenin enhanced ROS generation
and facilitated cytochrome crelease, which led to apoptosis only in
cancerous hepatocytes .
There are still few in vivo studies of apigenin as a potential HCC
chemopreventive agent. Wistar albino rats treated with apigenin dis-
played a decreased level of lipid peroxidation (LPO) and increased
antioxidant status in induced hepatocellular carcinoma . More-
over, a recent study by Li et al.  using bioluminescence and flu
orescence molecular imaging observed a significant inhibition of liver
tumour formation in apigenin-treated Balb/c nude mice (injected with
HepG2 HCC) in comparison with the control group.
2.8. Cervical and ovary cancer
Oral administration of apigenin has been shown to inhibit the
metastasis of ovarian cancer cell xenograft tumours in mice while in
vitro treatment supressed invasion and migration of ovarian cancer
cells. These effects were attributed to down-regulation of MMP-9 by
apigenin in exposed cells and tissues .
A study was designed to examine whether apigenin could be used
in the treatment of cervical cancer by targeting cervical CSC. Its re-
sults revealed that apigenin treatment inhibited the proliferation of
HeLa-derived sphere-forming cells (SFCs) and caused a loss of their
self-renewal capacity. The authors ascribed these antiproliferative ef-
fects of apigenin to the suppression of CK2, kinase associated with
maintenance of CSC properties . In a similar study, Tang et al.
 confirmed that apigenin was able to target cervical CSC using
SFCs derived from a SKOV3 cervical cancer cell line. Apigenin ex-
posure interfered with the self-renewal ability of SFCs through the de-
crease of CK2 expression and inactivation of Gli1, an oncogene in-
volved in the Hedgehog signalling pathway. Fig. 2.
The potential antiproliferative effects of apigenin have been re-
cently evaluated in chemoresistant ovarian cancer cells. Apigenin de-
creased the viability of both parental and chemoresistant SKOV3 cells
through the downregulation of TAM receptor tyrosine kinases ex-
pression. It also downregulated their downstream targets; Akt and
Bcl-xL . Furthermore, apigenin cytotoxic activity was recently
tested in a panel of cervical cancer cell lines. The findings indi-
cated that apigenin possessed a selective cytotoxic effect, which was
achieved through the elevation of ROS and LPO, and mitochondrial
Fig. 2. Schematic summary of apigenin targets.
Cancer Letters xxx (2017) xxx-xxx 7
membrane potential's decrease. Apigenin exposure also inhibited mi-
gration and invasion in cervical cancer cells . Table 1, Table 2.
3. Role of apigenin in chemotherapy
As was already mentioned in previous chapters, apigenin is able
to interact with compounds used in conventional drug chemother-
apy. Earlier studies have reported of the apigenin's ability to block
cytochrome P450 (CYP) enzymes, proteins involved in the metabo-
lism of many chemotherapeutics, which can overcome chemoresis-
tance in many cancer types . By doing so, apigenin augments
the anticancer activity of these drugs and decreases their negative ef-
fects [9,64]. A study by Johnson and de Mejia  described the in-
teractions between apigenin and various chemotherapeutics in PaCC.
Their results showed that apigenin pretreatment sensitized PaCC to
chemotherapeutics 5-FU and gemcitabine and enhanced their antipro-
liferative effect. A similar synergistic activity of apigenin and 5-FU
was observed in hepatocellular carcinoma where apigenin exposure
increased the cytotoxic activity of 5-FU through ROS elevation and
depolarization of mitochondrial membrane .
Furthermore, simultaneous administration of apigenin and pacli-
taxel, a widely used antimicrotubule chemotherapeutic, increased
half-life of paclitaxel, and elevated its oral bioavailability and in-
testinal absorption in rats . This was accomplished through api-
genin-mediated inhibition of CYP3A4 and P-glycoprotein (P-gp), a
transporter involved in the extrusion of paclitaxel from the intestines.
An earlier study by Choi and Choi , reported of apigenin affect-
ing the metabolism of oral paclitaxel, while the intravenously-admin-
istrated drug was not affected, proving that the improved bioavail-
ability was primarily due to apigenin's inhibition of P-gp and the
subsequent increased intestinal absorption. In another study, apigenin
modulated the pharmacokinetic characteristics of orally-administered
etoposide, topoisomerase II inhibitor, by suppressing P-gp and
CYP3A4 activity, which enhanced oral exposure and increased
plasma half-life and bioavailability of etoposide. At the same time,
body clearance of intravenous etoposide was partially down-regu-
lated by concurrent apigenin administration . A study designed to
analyse the interaction between raloxifene, a breast cancer chemother-
apeutic, and apigenin, demonstrated that co-administration of apigenin
increased the bioavailability of raloxifene in rats by competitively in-
hibiting its phase II conjugation (glucuronidation and sulfation) .
The ATP-binding cassette (ABC) transporter family are proteins
involved in the efflux of many chemotherapeutics and are often over-
expressed in multidrug-resistant (MDR) tumour cells. P-gp is a mem-
ber of the ABC family and is encoded by the ABCB1 gene. A study
conducted on docetaxel-resistant prostate cancer cells confirmed that
the overexpression of ABCB1 facilitated docetaxel resistance in those
cells. Exposure of resistant cells to apigenin down-regulated ABCB1
expression and re-established docetaxel sensitivity . Saeed et al.
 recently investigated the interaction between apigenin and ABC
transporters BCRP (breast cancer resistance protein), ABCB5 and
P-gp in chemotherapeutic-sensitive and -resistant cancer cell lines.
The findings of their in vitro study showed apigenin acting as a
multi-specific inhibitor of all three ABC transporters, which aug-
mented the intracellular concentration of doxorubicin and docetaxel
and improved drug cytotoxicity in chemoresistant cells. Moreover, in
silico molecular docking studies have indicated that apigenin binds to
transporters and interferes with ATP binding and cleavage, thus deny-
ing the energy necessary for the outward transport of chemotherapeu-
Although most studies report that apigenin possesses favourable
drug-drug interaction profile, it may also, in certain circumstances,
interfere with the activity of chemotherapeutics. The results of Ru-
ela-de-Sousa et al.  revealed that apigenin weakened the cy-
totoxic effect of the chemotherapeutic vincristine in leukemia cells
via the induction of autophagy and G0/G1 cell cycle arrest. As vin-
cristine acts by disrupting microtubules, the apigenin-mediated cell
cycle arrest disabled this mechanism and protected the cells from
vincristine-induced cell death. Furthermore, it has been shown that
long-term administration of apigenin accelerated the metabolism of
imatinib and consequently lowered its circulating concentration in
rats. Contrastingly, single-dose exposure to apigenin had a negative
effect on imatinib's metabolism which resulted in its increased
bioavailability and higher plasma concentrations .
4. Conclusions, knowledge gaps and future perspectives
In this review, we presented a summary of a number of articles
and studies which evaluated natural flavonoid apigenin as a compound
with great potential in chemotherapy of various types of cancer. Most
chemotherapeutics target and selectively kill cells that are dividing
rapidly. Unfortunately, normal fast-dividing cells such as hair follicles
and digestive epithelial cells are also affected during this approach.
For this reason, the focus of the research in the last few years has
been directed to the discovery and development of new generation of
chemotherapeutics that would target and exclusively kill only cancer
cells without any adverse effects in normal cells. Dietary flavonoids
such as apigenin represent an interesting link between diet and treat-
ment of chronic diseases including cancer.
Previous studies have discovered a presence of cells with stem-like
properties in hematopoietic and some solid tumours. It has been es-
tablished that those cancer stem cells (CSC) possess a self-renewing
capacity and can regenerate tumour, but to a lesser extent, because
they represent only a small fraction in tumour tissue. They share some
of the properties with normal stem cells such as resistance to apopto-
sis and drugs, which makes them an interesting target for anticancer
strategies. Evaluation of the currently available articles indicates that
apigenin can be used as an agent that targets CSC in various types of
cancer and in this way exerts its anticancer activity. Furthermore, api-
genin is able to synergistically augment the effect of chemotherapeu-
tics by overcoming the acquired resistance in cancer cells. It should be
noted that further in vivo studies are needed to confirm the apigenin
anticancer stem cell effect. Additionally, one of the present knowledge
gaps is apigenin's activity in normal stem cells, which should also be
evaluated in the future.
One of the promising future anticancer approaches is the induc-
tion of cellular senescence, reported here to be easily achieved by ex-
tended low-dose treatments of apigenin. This kind of chemotherapy
would selectively kill only those cells which are unable to respond
properly to induced stress, such as cancer cells, due to their genomic
instability. Another important issue which should be further explored
in the future studies is the ability of apigenin to act as a small-mole-
cule inhibitor. The studies reviewed so far show that apigenin down-
regulates several important proteins involved in the onset and pro-
gression of cancer, such as casein kinase 2 and histone deacetylases,
which can be exploited in the development of new anticancer thera-
pies. In this context, it is important to note the synergistic activity api-
genin displays when combined with the inhibitors of signalling path-
ways involved in carcinogenesis. Additionally, as mentioned in the
previous chapters, apigenin shows an interesting interaction with ep-
ithelial to mesenchymal transition, a process crucial in the invasion
and metastasis of cancer cells. Therefore, future efforts should focus
8 Cancer Letters xxx (2017) xxx-xxx
Targets and mechanisms of apigenin activity in cancers.
Mechanism Effect Targets References
decreased expression and/or activity Bcl-2 [28,30–33,35,40,51,59,61,64,70,76,78,87,90,97,99]
XIAP, cIAP-1 and -2 [61,87]
HDAC-1 and -3 [56,59,61]
Axl, Tyro-3 
GSH, SOD 
increased expression and/or activity Bax, Bim, Bid [28–33,51,59,61,62,64,69,73,74,76,78,90,97]
Noxa, Puma [32,84]
Caspase-3, -6, -7, -8, -9 [28–34,38,47–51,61,74,75,78,87,88,90,91,95,97–99]
miR-16 and -138 [31,40]
decreased expression and/or activity p62 
increased expression and/or activity LC3-II [36,51,75]
decreased expression and/or activity pRb 
Cyclin A, B1, D1 and E [29,37,56,64,72,75,76,87]
CDK-1, -2, and -4 [29,37,56,75]
increased expression and/or activity p16, p21 and p27 [29,47,48,56,59,62,69,70,75,76,84]
altered phosphorylation p53 [33,47,48,50]
altered cellular location p53 
Angiogenesis, metastasis and invasion
decreased expression and/or activity VEGF [30,45,46,48–50,64,65,92,93]
MMP-2 and -9 [29,30,32,40,50,69,71,93,104]
Snail, Slug [66,69,70,100]
Oct-3 and -4 
CD44, 105 and 133 [44,45]
Integrin subunits 
increased expression and/or activity E-cadherin [30,66,93,100]
Cancer Letters xxx (2017) xxx-xxx 9
Table 1 (Continued)
Mechanism Effect Targets References
altered phosphorylation Smad-2 and -3 
altered cellular location Smad-2 and -3 
Signalling pathways modulated by apigenin activity
Apigenin concentration ranges used in reviewed cancer studies.
Study type Dose References Study type Dose References
in vitro 1-10 μM [92,97] in vivo 20 or 50 μg/mouse/d [58,59,61–64]
1-20 μM [60,62,63,78,89,104] 50 or 100 μg/mouse/d 
1-30 μM [73,98] 20 mg/kg/w 
1-40 μM [47,56,59,61,105–107] 5 or 25 mg/kg/d 
3-50 μM [28,32,38,52,54,65,75,91] 25 mg/kg/t.i.w. 
10-60 μM  15 or 30 mg/kg/d 
2-80 μM [33,35,51,66,67,72,88] 25 mg/kg/d 
1-100 μM [34,36,37,39,43–45,48–50,53,76,84,85,87,99,108] 50 mg/kg/d [46,71]
10-160 μM [41,71,74,90] 75, 150 mg/kg/d 
10-200 μM  150 mg/kg/d 
40-280 μM  200 or 300 mg/kg/d 
/d: once daily; /w: once per week; t.i.w.: three times per week.
on identifying the precise mechanisms behind this interaction. An-
other relevant subject for future research will be apigenin's role in the
anticancer immune response, an activity which was observed in sev-
eral different cancer types. Many studies reviewed here reveal that api-
genin treatment induces both apoptosis and autophagy in cancer cells.
Consequently, a better clarification of the interplay between these two
cell death modes in apigenin-treated cancer cells is needed to better
understand apigenin's role in cell death induction.
In conclusion, a few unanswered questions remain before we can
start using apigenin as a chemopreventive and chemotherapeutic
agent, specifically; its limited bioavailability and poor absorption in
humans, limited data on pharmacokinetics and accumulation in or-
gan sites, lack of specific cellular targets, toxicological safety and in-
consistency between in vivo and in vitro therapeutic dosage. Even
with these uncertainties and aforementioned knowledge gaps, the as-
sessment of the existing literature indicates that this natural flavonoid
could be used as an effective chemopreventive and possible anticancer
agent. The beneficial effects of apigenin are indeed promising but they
require further in vitro and in vivo studies to enable its translation from
bench to bedside.
Conflict of interest
The authors declare that they have no conflict of interest.
Supported by the University of Zagreb, Faculty of Science and the
Institute for Medical Research and Occupational Health.
 R.L. Siegel, K.D. Miller, A. Jemal, Cancer statistics, 2016, CA, Cancer J. Clin.
66 (2016) 7–30, https://doi.org/10.3322/caac.21332.
 D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell
144 (2011) 646–674, https://doi.org/10.1016/j.cell.2011.02.013.
 S. Singh, B. Sharma, S.S. Kanwar, A. Kumar, Lead phytochemicals for anti-
cancer drug development, Front. Plant Sci. 7 (2016) 1–13, https://doi.org/10.
 Y. Zhou, J. Zheng, Y. Li, D.-P. Xu, S. Li, Y.-M. Chen, H.-B. Li, Natural
polyphenols for prevention and treatment of cancer, Nutrients 8 (2016) 515,
 É.C. Lefort, J. Blay, Apigenin and its impact on gastrointestinal cancers, Mol.
Nutr. Food Res. 57 (2013) 126–144, https://doi.org/10.1002/mnfr.201200424.
 K. Ferrini, F. Ghelfi, R. Mannucci, L. Titta, Lifestyle, nutrition and breast can-
cer: facts and presumptions for consideration, Ecancermedicalscience 9 (2015)
 A.F. Abdull Razis, N. Mohd Noor, Cruciferous vegetables: dietary phytochemi-
cals for cancer prevention, Asian Pac. J. Cancer Prev. 14 (2013) 1565–1570,
 J.V. Higdon, B. Delage, D.E. Williams, R.H. Dashwood, Cruciferous vegeta-
bles and human cancer risk: epidemiologic evidence and mechanistic basis,
10 Cancer Letters xxx (2017) xxx-xxx
Pharmacol. Res. 55 (2007) 224–236, https://doi.org/10.1016/j.phrs.2007.01.
 D. Tang, K. Chen, L. Huang, J. Li, Pharmacokinetic properties and drug inter-
actions of apigenin, a natural flavone, Expert Opin. Drug Metab. Toxicol.
13 (2017) 323–330, https://doi.org/10.1080/17425255.2017.1251903.
 A. Abdal Dayem, H.Y. Choi, G.-M. Yang, K. Kim, S.K. Saha, S.-G. Cho, The
anti-cancer effect of polyphenols against breast cancer and cancer stem cells:
molecular mechanisms, Nutrients 8 (2016) 581, https://doi.org/10.3390/
 G. Carruba, L. Cocciadiferro, A. Di Cristina, O.M. Granata, C. Dolcemascolo,
I. Campisi, M. Zarcone, M. Cinquegrani, A. Traina, Nutrition, aging and can-
cer: lessons from dietary intervention studies, Immun. Ageing. 13 (2016) 13,
 K. Sak, Cytotoxicity of dietary flavonoids on different human cancer types,
Pharmacogn. Rev. 8 (2014) 122–146, https://doi.org/10.4103/0973-7847.
 B. Sung, H.Y. Chung, N.D. Kim, Role of apigenin in cancer prevention via the
induction of apoptosis and autophagy, J. Cancer Prev. 21 (2016) 216–226.
 H.U. Simon, A. Haj-Yehia, F. Levi-Schaffer, Role of reactive oxygen species
(ROS) in apoptosis induction, Apoptosis 5 (2000) 415–418, https://doi.org/10.
 M.J. Bak, S. Das Gupta, J. Wahler, N. Suh, Role of dietary bioactive natural
products in estrogen receptor-positive breast cancer, Semin. Cancer Biol.
40–41 (2016) 170–191, https://doi.org/10.1016/j.semcancer.2016.03.001.
 V. Spicak, F. Subrt, Effect of apigenin on histamine liberation, Ceskoslov. Fys-
iol. 7 (1958) 263–264.
 D.F. Birt, B. Walker, M.G. Tibbels, E. Bresnick, Anti-mutagenesis and
anti-promotion by apigenin, robinetin and indole-3-carbinol, Carcinogenesis
7 (1986) 959–963.
 S. Gupta, F. Afaq, H. Mukhtar, Selective growth-inhibitory, cell-cycle deregu-
latory and apoptotic response of apigenin in normal versus human prostate car-
cinoma cells, Biochem. Biophys. Res. Commun. 287 (2001) 914–920, https://
 S. Shukla, S. Gupta, Apigenin: a promising molecule for cancer prevention,
Pharm. Res. 27 (2010) 962–978, https://doi.org/10.1007/s11095-010-0089-7.
 H.-Y. Kim, O.-H. Kim, M.-K. Sung, Effects of phenol-depleted and phenol-rich
diets on blood markers of oxidative stress, and urinary excretion of quercetin
and kaempferol in healthy volunteers, J. Am. Coll. Nutr. 22 (2003) 217–223,
 C.S. Yang, J.M. Landau, M.T. Huang, H.L. Newmark, Inhibition of carcino-
genesis by dietary polyphenolic compounds, Annu. Rev. Nutr. 21 (2001)
 J. O'Prey, J. Brown, J. Fleming, P.R. Harrison, Effects of dietary flavonoids on
major signal transduction pathways in human epithelial cells, Biochem. Phar-
macol. 66 (2003) 2075–2088, https://doi.org/10.1016/j.bcp.2003.07.007.
 A. Thiery-Vuillemin, T. Nguyen, X. Pivot, J.P. Spano, A. Dufresnne, J.C. So-
ria, Molecularly targeted agents: their promise as cancer chemopreventive inter-
ventions, Eur. J. Cancer 41 (2005) 2003–2015, https://doi.org/10.1016/j.ejca.
 S.E. Nielsen, J.F. Young, B. Daneshvar, S.T. Lauridsen, P. Knuthsen, B. Sand-
ström, L.O. Dragsted, Effect of parsley (Petroselinum crispum) intake on uri-
nary apigenin excretion, blood antioxidant enzymes and biomarkers for oxida-
tive stress in human subjects, Br. J. Nutr. 81 (1999) 447–455, https://doi.org/10.
 Y.-J. Surh, Cancer chemoprevention with dietary phytochemicals, Nat. Rev.
Cancer 3 (2003) 768–780, https://doi.org/10.1038/nrc1189.
 Y. Arai, S. Watanabe, M. Kimira, K. Shimoi, R. Mochizuki, N. Kinae, Dietary
intakes of flavonols, flavones and isoflavones by Japanese women and the in-
verse correlation between quercetin intake and plasma LDL cholesterol concen-
tration, J. Nutr. 130 (2000) 2243–2250.
 K. Janssen, R.P. Mensink, F.J.J. Cox, J.L. Harryvan, R. Hovenier, P.C.H. Holl-
man, M.B. Katan, Effects of the flavonoids quercetin and apigenin on hemosta-
sis in healthy volunteers: results from an in vitro and a dietary supplement
study, Am. J. Clin. Nutr. 67 (1998) 255–262.
 L.-P. Chan, T.-H. Chou, H.-Y. Ding, P.-R. Chen, F.-Y. Chiang, P.-L. Kuo,
C.-H. Liang, Apigenin induces apoptosis via tumor necrosis factor receptor-
and Bcl-2-mediated pathway and enhances susceptibility of head and neck
squamous cell carcinoma to 5-fluorouracil and cisplatin, Biochim. Biophys.
Acta Gen. Subj. 1820 (2012) 1081–1091, https://doi.org/10.1016/j.bbagen.
 M. Chakrabarti, N.L. Banik, S.K. Ray, Sequential hTERT knockdown and api-
genin treatment inhibited invasion and proliferation and induced apoptosis in
human malignant neuroblastoma SK-N-DZ and SK-N-BE2 cells, J. Mol. Neu-
rosci. 51 (2013) 187–198, https://doi.org/10.1007/s12031-013-9975-x.
 M.M. Hossain, N.L. Banik, S.K. Ray, N-Myc knockdown and apigenin treat-
ment controlled growth of malignant neuroblastoma cells having N-Myc ampli-
fication, Gene 529 (2013) 27–36, https://doi.org/10.1016/j.gene.2013.07.094.
 M. Chakrabarti, N.L. Banik, S.K. Ray, miR-138 overexpression is more power-
ful than hTERT knockdown to potentiate apigenin for apoptosis in neuroblas
toma in vitro and in vivo, Exp. Cell Res. 319 (2013) 1575–1585, https://doi.org/
 N. Mohan, W. Ai, M. Chakrabarti, N.L. Banik, S.K. Ray, KLF4 overexpression
and apigenin treatment down regulated anti-apoptotic Bcl-2 proteins and matrix
metalloproteinases to control growth of human malignant neuroblastoma
SK-N-DZ and IMR-32 cells, Mol. Oncol. 7 (2013) 464–474, https://doi.org/10.
 S.H. Kim, J.G. Kang, C.S. Kim, S.-H. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Api-
genin induces c-Myc-mediated apoptosis in FRO anaplastic thyroid carcinoma
cells, Mol. Cell. Endocrinol. 369 (2013) 130–139, https://doi.org/10.1016/j.
 S.H. Kim, J.G. Kang, C.S. Kim, S.H. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Akt
inhibition enhances the cytotoxic effect of apigenin in combination with
PLX4032 in anaplastic thyroid carcinoma cells harboring BRAFV600E, J. En-
docrinol. Invest. 36 (2013) 1099–1104, https://doi.org/10.3275/9099.
 S.H. Kim, J.G. Kang, C.S. Kim, S. Ihm, M.G. Choi, H.J. Yoo, S.J. Lee, Sup-
pression of akt potentiates synergistic cytotoxicity of apigenin with TRAIL in
anaplastic thyroid carcinoma cells, Anticancer Res. 35 (2015) 6529–6537.
 L. Zhang, X. Cheng, Y. Gao, J. Zheng, Q. Xu, Y. Sun, H. Guan, H. Yu, Z. Sun,
Apigenin induces autophagic cell death in human papillary thyroid carcinoma
BCPAP cells, Food Funct. 6 (2015) 3464–3472, https://doi.org/10.1039/
 D. Maggioni, W. Garavello, R. Rigolio, L. Pignataro, R. Gaini, G. Nicolini,
Apigenin impairs oral squamous cell carcinoma growth in vitro inducing cell
cycle arrest and apoptosis, Int. J. Oncol. 43 (2013) 1675–1682, https://doi.org/
 Y. Wang, Y.S. Xu, L.H. Yin, L.N. Xu, J.Y. Peng, H. Zhou, W. Kang, Synergis-
tic anti-glioma effect of Hydroxygenkwanin and Apigenin in vitro, Chem. Biol.
Interact. 206 (2013) 346–355, https://doi.org/10.1016/j.cbi.2013.10.009.
 P.L.C. Coelho, M.N. Oliveira, A.B. da Silva, B.P.S. Pitanga, V.D.A. Silva, G.P.
Faria, G.P. Sampaio, M. de F.D. Costa, S. Braga-de-Souza, S.L. Costa, The
flavonoid apigenin from Croton betulaster Mull inhibits proliferation, induces
differentiation and regulates the inflammatory profile of glioma cells, Anti-
cancer Drugs 27 (2016) 960–969, https://doi.org/10.1097/CAD.
 X. Chen, M. Wu, D. Li, J. You, Apigenin inhibits glioma cell growth through
promoting microRNA-16 and suppression of BCL-2 and nuclear factor-κB/
MMP-9, Mol. Med. Rep. 14 (2016) 2352–2358, https://doi.org/10.3892/mmr.
 Y.Y. Xu, T.T. Wu, S.H. Zhou, Y.Y. Bao, Q.Y. Wang, J. Fan, Y.P. Huang, Api-
genin suppresses GLUT-1 and p-AKT expression to enhance the chemosensi-
tivity to cisplatin of laryngeal carcinoma Hep-2 cells: an in vitro study, Int. J.
Clin. Exp. Pathol. 7 (2014) 3938–3947.
 Y.-Y. Bao, S.-H. Zhou, Z.-J. Lu, J. Fan, Y.-P. Huang, Inhibiting GLUT-1 ex-
pression and PI3K/Akt signaling using apigenin improves the radiosensitivity
of laryngeal carcinoma in vivo, Oncol. Rep. 34 (2015) 1805–1814, https://doi.
 H. Zhu, H. Jin, J. Pi, H. Bai, F. Yang, C. Wu, J. Jiang, J. Cai, Apigenin induced
apoptosis in esophageal carcinoma cells by destruction membrane structures,
Scanning 38 (2016) 322–328, https://doi.org/10.1002/sca.21273.
 B. Kim, N. Jung, S. Lee, J.K. Sohng, H.J. Jung, Apigenin inhibits cancer stem
cell-like phenotypes in human glioblastoma cells via suppression of c-met sig-
naling, Phyther. Res. 30 (2016) 1833–1840, https://doi.org/10.1002/ptr.5689.
 Y. Ketkaew, T. Osathanon, P. Pavasant, S. Sooampon, Apigenin inhibited hy-
poxia induced stem cell marker expression in a head and neck squamous cell
carcinoma cell line, Arch. Oral Biol. 74 (2017) 69–74, https://doi.org/10.1016/j.
 B. Mafuvadze, Y. Liang, C. Besch-Williford, X. Zhang, S.M. Hyder, Apigenin
induces apoptosis and blocks growth of medroxyprogesterone acetate-depen-
dent BT-474 xenograft tumors, Horm. Cancer 3 (2012) 160–171, https://doi.
 H.-S. Seo, H.-S. Choi, S.-R. Kim, Y.K. Choi, S.-M. Woo, I. Shin, J.-K. Woo,
S.-Y. Park, Y.C. Shin, S.-G. Ko, Apigenin induces apoptosis via extrinsic path-
way, inducing p53 and inhibiting STAT3 and NFκB signaling in HER2-overex-
pressing breast cancer cells, Mol. Cell. Biochem. 366 (2012) 319–334, https://
 H.-S. Seo, J.M. Ku, H.-S. Choi, J.-K. Woo, B.-H. Jang, Y.C. Shin, S.-G. Ko,
Induction of caspase-dependent apoptosis by apigenin by inhibiting STAT3 sig-
naling in HER2-overexpressing MDA-MB-453 breast cancer cells, Anticancer
Res. 34 (2014) 2869–2882.
 H.-S. Seo, J.M. Ku, H.S. Choi, J.K. Woo, B.H. Jang, H. Go, Y.C. Shin, S.-G.
Ko, Apigenin induces caspase-dependent apoptosis by inhibiting signal trans-
ducer and activator of transcription 3 signaling in HER2-overexpressing
SKBR3 breast cancer cells, Mol. Med. Rep. 12 (2015) 2977–2984, https://doi.
 H.-S. Seo, J.M. Ku, H.-S. Choi, Y.K. Choi, J.-K. Woo, J.K. Jo, K.W. Nam, N.
Park, B.-H. Jang, Y.C. Shin, S.-G. Ko, Induction of caspase-dependent extrin-
sic apoptosis by apigenin through inhibition of signal transducer and activator
of transcription 3 (STAT3) signaling in HER2-overexpressing BT-474 breast
Cancer Letters xxx (2017) xxx-xxx 11
cancer cells, Biosci. Rep. 3 (2015) https://doi.org/10.1042/BSR20150165,
 X. Cao, B. Liu, W. Cao, W. Zhang, F. Zhang, H. Zhao, R. Meng, L. Zhang, R.
Niu, X. Hao, B. Zhang, Autophagy inhibition enhances apigenin-induced apop-
tosis in human breast cancer cells, Chin. J. Cancer Res. 25 (2013) 212–222,
 M.E. Harrison, M.R. Power Coombs, L.M. Delaney, D.W. Hoskin, Exposure of
breast cancer cells to a subcytotoxic dose of apigenin causes growth inhibition,
oxidative stress, and hypophosphorylation of Akt, Exp. Mol. Pathol. 97 (2014)
 H. Bai, H. Jin, F. Yang, H. Zhu, J. Cai, Apigenin induced MCF-7 cell apopto-
sis-associated reactive oxygen species, Scanning 36 (2014) 622–631, https://
 A.M. Scherbakov, O.E. Andreeva, Apigenin inhibits growth of breast cancer
cells: the role of ERα and HER2/neu, Acta Naturae 7 (2015) 133–139.
 M.R.P. Coombs, M.E. Harrison, D.W. Hoskin, Apigenin inhibits the inducible
expression of programmed death ligand 1 by human and mouse mammary car-
cinoma cells, Cancer Lett. 380 (2016) 424–433, https://doi.org/10.1016/j.canlet.
 T.-H. Tseng, M.-H. Chien, W.-L. Lin, Y.-C. Wen, J.-M. Chow, C.-K. Chen,
T.-C. Kuo, W.-J. Lee, Inhibition of MDA-MB-231 breast cancer cell prolifera-
tion and tumor growth by apigenin through induction of G2/M arrest and his-
tone H3 acetylation-mediated p21(WAF1/CIP1) expression, Environ. Toxicol.
32 (2017) 434–444, https://doi.org/10.1002/tox.22247.
 M.A. Babcook, S. Gupta, Apigenin modulates insulin-like growth factor Axis:
implications for prevention and therapy of prostate cancer, Curr. Drug Targets
257 (2012) 2432–2437, https://doi.org/10.1016/j.immuni.2010.12.017.
 S. Shukla, G.T. MacLennan, P. Fu, S. Gupta, Apigenin attenuates insulin-like
growth Factor-I signaling in an autochthonous mouse prostate cancer model,
Pharm. Res. 29 (2012) 1506–1517, https://doi.org/10.1007/s11095-011-0625-0.
 M. Pandey, P. Kaur, S. Shukla, A. Abbas, P. Fu, S. Gupta, Plant flavone api-
genin inhibits HDAC and remodels chromatin to induce growth arrest and
apoptosis in human prostate cancer cells: in vitro and in vivo study, Mol. Car-
cinog. 51 (2012) 952–962, https://doi.org/10.1002/mc.20866.
 M. Oishi, Y. Iizumi, T. Taniguchi, W. Goi, T. Miki, T. Sakai, Apigenin sensi-
tizes prostate cancer cells to Apo2L/TRAIL by targeting adenine nucleotide
translocase-2, PLoS One 8 (2013) https://doi.org/10.1371/journal.pone.
 S. Shukla, P. Fu, S. Gupta, Apigenin induces apoptosis by targeting inhibitor of
apoptosis proteins and Ku70-Bax interaction in prostate cancer, Apoptosis
19 (2014) 883–894, https://doi.org/10.1007/s10495-014-0971-6.
 S. Shukla, N. Bhaskaran, M.A. Babcook, P. Fu, G.T. Maclennan, S. Gupta,
Apigenin inhibits prostate cancer progression in TRAMP mice via targeting
PI3K/Akt/FoxO pathway, Carcinogenesis 35 (2014) 452–460, https://doi.org/
 S. Shukla, R. Kanwal, E. Shankar, M. Datt, M.R. Chance, P. Fu, G.T. MacLen-
nan, S. Gupta, Apigenin blocks IKKα activation and suppresses prostate cancer
progression, Oncotarget 6 (2015) 31216–31232, https://doi.org/10.18632/
 S. Shukla, E. Shankar, P. Fu, G.T. MacLennan, S. Gupta, Suppression of NF-κb
and NF-κb-regulated gene expression by apigenin through IκBα and IKK path-
way in TRAMP mice, PLoS One 10 (2015) https://doi.org/10.1371/journal.
 S. Mirzoeva, C.A. Franzen, J.C. Pelling, Apigenin inhibits TGF-β-induced
VEGF expression in human prostate carcinoma cells via a Smad2/3- and
Src-dependent mechanism, Mol. Carcinog. 53 (2014) 598–609, https://doi.org/
 Y. Zhu, J. Wu, S. Li, X. Wang, Z. Liang, X. Xu, X. Xu, Z. Hu, Y. Lin, H.
Chen, J. Qin, Q. Mao, L. Xie, Apigenin inhibits migration and invasion via
modulation of epithelial mesenchymal transition in prostate cancer, Mol. Med.
Rep. 11 (2015) 1004–1008, https://doi.org/10.3892/mmr.2014.2801.
 V. Singh, V. Sharma, V. Verma, D. Pandey, S.K. Yadav, J.P. Maikhuri, G.
Gupta, Apigenin manipulates the ubiquitin-proteasome system to rescue estro-
gen receptor-β from degradation and induce apoptosis in prostate cancer cells,
Eur. J. Nutr. 54 (2015) 1255–1267, https://doi.org/10.1007/s00394-014-0803-z.
 X. Wang, G. Wang, X. Li, J. Liu, T. Hong, Q. Zhu, P. Huang, R.S. Ge, Sup-
pression of rat and human androgen biosynthetic enzymes by apigenin: possible
use for the treatment of prostate cancer, Fitoterapia 111 (2016) 66–72, https://
 S. Erdogan, O. Doganlar, Z.B. Doganlar, R. Serttas, K. Turkekul, I. Dibirdik,
A. Bilir, The flavonoid apigenin reduces prostate cancer CD44+ stem cell sur-
vival and migration through PI3K/Akt/NF-kB signaling, Life Sci. 162 (2016)
 S. Erdogan, K. Turkekul, R. Serttas, Z. Erdogan, The natural flavonoid api-
genin sensitizes human CD44+ prostate cancer stem cells to cisplatin therapy,
Biomed. Pharmacother. 88 (2017) 210–217, https://doi.org/10.1016/j.biopha.
 L. Chunhua, L. Donglan, F. Xiuqiong, Z. Lihua, F. Qin, L. Yawei, Z. Liang, W.
Ge, J. Linlin, Z. Ping, L. Kun, S. Xuegang, Apigenin up-regulates transgelin
and inhibits invasion and migration of colorectal cancer through decreased
phosphorylation of AKT, J. Nutr. Biochem. 24 (2013) 1766–1775, https://doi.
 M. Xu, S. Wang, Y. Song, J. Yao, K. Huang, X. Zhu, Apigenin suppresses col-
orectal cancer cell proliferation, migration and invasion via inhibition of the
Wnt/β-catenin signaling pathway, Oncol. Lett. 11 (2016) 3075–3080, https://
 H. Shao, K. Jing, E. Mahmoud, H. Huang, X. Fang, C. Yu, Apigenin sensitizes
colon cancer cells to antitumor activity of ABT-263, Mol. Cancer Ther.
12 (2013) 2640–2650, https://doi.org/10.1158/1535-7163.MCT-13-0066.
 B. Wang, X.-H. Zhao, Apigenin induces both intrinsic and extrinsic pathways
of apoptosis in human colon carcinoma HCT-116 cells, Oncol. Rep. 37 (2017)
 Y. Lee, B. Sung, Y.J. Kang, D.H. Kim, J.Y. Jang, S.Y. Hwang, M. Kim, H.S.
Lim, J.H. Yoon, H.Y. Chung, N.D. Kim, Apigenin-induced apoptosis is en-
hanced by inhibition of autophagy formation in HCT116 human colon cancer
cells, Int. J. Oncol. 44 (2014) 1599–1606, https://doi.org/10.3892/ijo.2014.
 K. Banerjee, M. Mandal, Oxidative stress triggered by naturally occurring
flavone apigenin results in senescence and chemotherapeutic effect in human
colorectal cancer cells, Redox Biol. 5 (2015) 153–162, https://doi.org/10.1016/
 J. Dai, P.G. Van Wie, L.Y. Fai, D. Kim, L. Wang, P. Poyil, J. Luo, Z. Zhang,
Downregulation of NEDD9 by apigenin suppresses migration, invasion, and
metastasis of colorectal cancer cells, Toxicol. Appl. Pharmacol. 311 (2016)
 J. Chen, J. Chen, Z. Li, C. Liu, L. Yin, The apoptotic effect of apigenin on hu-
man gastric carcinoma cells through mitochondrial signal pathway, Tumor
Biol. 35 (2014) 7719–7726, https://doi.org/10.1007/s13277-014-2014-x.
 A. Tatsuta, H. Iishi, M. Baba, H. Yano, K. Murata, M. Mukai, H. Akedo, Sup-
pression by apigenin of peritoneal metastasis of intestinal adenocarcinomas in-
duced by azoxymethane in Wistar rats, Clin. Exp. Metastasis 18 (2000)
 A. Au, B. Li, W. Wang, H. Roy, K. Koehler, D. Birt, Effect of dietary apigenin
on colonic ornithine decarboxylase activity, aberrant crypt foci formation, and
tumorigenesis in different experimental models, Nutr. Cancer 54 (2006)
 T. Leonardi, J. Vanamala, S.S. Taddeo, L.A. Davidson, M.E. Murphy, B.S.
Patil, N. Wang, R.J. Carroll, R.S. Chapkin, J.R. Lupton, N.D. Turner, Apigenin
and naringenin suppress colon carcinogenesis through the aberrant crypt stage
in azoxymethane-treated rats, Exp. Biol. Med. (Maywood) 235 (2010)
 Y. Zhong, C. Krisanapun, S.-H. Lee, T. Nualsanit, C. Sams, P. Peungvicha, S.J.
Baek, Molecular targets of apigenin in colorectal cancer cells: involvement of
p21, NAG-1 and p53, Eur. J. Cancer 46 (2010) 3365–3374, https://doi.org/10.
 K. Banerjee, S. Banerjee, M. Mandal, Enhanced chemotherapeutic efficacy of
apigenin liposomes in colorectal cancer based on flavone-membrane interac-
tions, J. Colloid Interface Sci. 491 (2017) 98–110, https://doi.org/10.1016/j.jcis.
 J.C. King, Q.Y. Lu, G. Li, A. Moro, H. Takahashi, M. Chen, V.L.W. Go, H.A.
Reber, G. Eibl, O.J. Hines, Evidence for activation of mutated p53 by apigenin
in human pancreatic cancer, Biochim. Biophys. Acta Mol. Cell Res.
1823 (2012) 593–604, https://doi.org/10.1016/j.bbamcr.2011.12.008.
 H. Pham, M. Chen, H. Takahashi, J. King, H.A. Reber, O.J. Hines, S. Pandol,
G. Eibl, Apigenin inhibits NNK-induced focal adhesion kinase activation in
pancreatic cancer cells, Pancreas 41 (2012) 1306–1315, https://doi.org/10.1097/
 J.L. Johnson, E.G. de Mejia, Interactions between dietary flavonoids apigenin
or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on
human pancreatic cancer cells, in vitro, Food Chem. Toxicol. 60 (2013) 83–91,
 J.L. Johnson, E.G. de Mejia, Flavonoid apigenin modified gene expression as-
sociated with inflammation and cancer and induced apoptosis in human pancre-
atic cancer cells through inhibition of GSK-3β/NF-κB signaling cascade, Mol.
Nutr. Food Res. 57 (2013) 2112–2127, https://doi.org/10.1002/mnfr.
 D.-G. Wu, P. Yu, J.-W. Li, P. Jiang, J. Sun, H.-Z. Wang, L.-D. Zhang, M.-B.
Wen, P. Bie, Apigenin potentiates the growth inhibitory effects by IKK-β-me-
diated NF-κB activation in pancreatic cancer cells, Toxicol. Lett. 224 (2014)
 N. Nelson, K. Szekeres, C. Iclozan, I.O. Rivera, A. McGill, G. Johnson, O.
Nwogu, T. Ghansah, Apigenin: selective CK2 inhibitor increases Ikaros expres-
sion and improves T cell homeostasis and function in murine pancreatic cancer,
PLoS One 12 (2017) https://doi.org/10.1371/journal.pone.0170197, e0170197.
 S. Das, J. Das, A. Samadder, N. Boujedaini, A.R. Khuda-Bukhsh, Apigenin-in-
duced apoptosis in A375 and A549 cells through selective action and dysfunc-
tion of mitochondria, Exp. Biol. Med. (Maywood) 237 (2012) 1433–1448,
12 Cancer Letters xxx (2017) xxx-xxx
 M.A. Hasnat, M. Pervin, J.H. Lim, B.O. Lim, Apigenin attenuates melanoma
cell migration by inducing anoikis through integrin and focal adhesion kinase
inhibition, Molecules 20 (2015) 21157–21166, https://doi.org/10.3390/
 S.-C. Chao, S.-C. Huang, D.-N. Hu, H.-Y. Lin, Subtoxic levels of apigenin in-
hibit expression and secretion of VEGF by uveal melanoma cells via suppres-
sion of ERK1/2 and PI3K/akt pathways, Evid. Based. Complement. Altern.
Med. 2013 (2013)817674https://doi.org/10.1155/2013/817674.
 H.-H. Cao, J.-H. Chu, H.-Y. Kwan, T. Su, H. Yu, C.-Y. Cheng, X.-Q. Fu, H.
Guo, T. Li, A.K.-W. Tse, G.-X. Chou, H.-B. Mo, Z.-L. Yu, Inhibition of the
STAT3 signaling pathway contributes to apigenin-mediated anti-metastatic ef-
fect in melanoma, Sci. Rep. 6 (2016) 21731, https://doi.org/10.1038/srep21731.
 N. Nasr Bouzaiene, F. Chaabane, A. Sassi, L. Chekir-Ghedira, K. Ghedira, Ef-
fect of apigenin-7-glucoside, genkwanin and naringenin on tyrosinase activity
and melanin synthesis in B16F10 melanoma cells, Life Sci. 144 (2016) 80–85,
 G. Zhao, X. Han, W. Cheng, J. Ni, Y. Zhang, J. Lin, Z. Song, Apigenin inhibits
proliferation and invasion, and induces apoptosis and cell cycle arrest in human
melanoma cells, Oncol. Rep. 37 (2017) 2277–2285, https://doi.org/10.3892/or.
 A.J. Kiraly, E. Soliman, A. Jenkins, R.T. Van Dross, Apigenin inhibits COX-2,
PGE2, and EP1 and also initiates terminal differentiation in the epidermis of tu-
mor bearing mice, Prostagl. Leukot. Essent. Fat. Acids 104 (2016) 44–53, https:
 E.Y. Kim, A.K. Kim, Apigenin sensitizes Huh-7 human hepatocellular carci-
noma cells to TRAIL-induced apoptosis, Biomol. Ther. Seoul. 20 (2012)
 E.Y. Kim, J.S. Yu, M. Yang, A.K. Kim, Sub-toxic dose of apigenin sensitizes
HepG2 cells to TRAIL through ERK-dependent up-regulation of TRAIL recep-
tor DR5, Mol. Cells 35 (2013) 32–40, https://doi.org/10.1007/
 X.-Y. Hu, J.-Y. Liang, X.-J. Guo, L. Liu, Y.-B. Guo, 5-Fluorouracil combined
with apigenin enhances anticancer activity through mitochondrial membrane
potential (ΔΨm)-mediated apoptosis in hepatocellular carcinoma, Clin. Exp.
Pharmacol. Physiol. 42 (2015) 146–153, https://doi.org/10.1111/1440-1681.
 Y. Qin, D. Zhao, H.G. Zhou, X.H. Wang, W.L. Zhong, S. Chen, W.G. Gu, W.
Wang, C.H. Zhang, Y.R. Liu, H.J. Liu, Q. Zhang, Y.Q. Guo, T. Sun, C. Yang,
Apigenin inhibits NF-kappaB and Snail signaling, EMT and metastasis in hu-
man hepatocellular carcinoma, Oncotarget 7 (2016) 41421–41431, https://doi.
 E. Seydi, H.R. Rasekh, A. Salimi, Z. Mohsenifar, J. Pourahmad, Selective toxi-
city of apigenin on cancerous hepatocytes by directly targeting their mitochon-
dria, Anticancer. Agents Med. Chem. 16 (2016) 1576–1586.
 J.P.V. Singh, K. Selvendiran, S.M. Banu, R. Padmavathi, D. Sakthisekaran,
Protective role of Apigenin on the status of lipid peroxidation and antioxidant
defense against hepatocarcinogenesis in Wistar albino rats, Phytomedicine
11 (2004) 309–314, https://doi.org/10.1078/0944711041495254.
 G. Li, C.-W. Chi, X.-F. Shao, C.-H. Fang, Application of molecular imaging
technology in evaluating the inhibiting effect of apigenin in vivo on subcuta-
neous hepatocellular carcinoma, Biochem. Biophys. Res. Commun. 487 (2017)
 J. He, Q. Xu, M. Wang, C. Li, X. Qian, Z. Shi, L.-Z. Liu, B.-H. Jiang, Oral ad-
ministration of apigenin inhibits metastasis through AKT/P70S6K1/MMP-9
pathway in orthotopic ovarian tumor model, Int. J. Mol. Sci. 13 (2012)
 J. Liu, X.-C. Cao, Q. Xiao, M.-F. Quan, Apigenin inhibits HeLa sphere-form-
ing cells through inactivation of casein kinase 2α, Mol. Med. Rep. 11 (2015)
 A.-Q. Tang, X.-C. Cao, L. Tian, L. He, F. Liu, Apigenin inhibits the self-re-
newal capacity of human ovarian cancer SKOV3-derived sphere-forming cells,
Mol. Med. Rep. 11 (2015) 2221–2226, https://doi.org/10.3892/mmr.2014.2974.
 Y.A. Suh, S.Y. Jo, H.Y. Lee, C. Lee, Inhibition of IL-6/STAT3 axis and target-
ing Axl and Tyro3 receptor tyrosine kinases by apigenin circumvent taxol resis-
tance in ovarian cancer cells, Int. J. Oncol. 46 (2015) 1405–1411, https://doi.
 R.P. Souza, P. de S. Bonfim-Mendonça, F. Gimenes, B.A. Ratti, V. Kaplum,
M.L. Bruschi, C.V. Nakamura, S.O. Silva, S.S. Maria-Engler, M.E.L. Conso-
laro, Oxidative stress triggered by apigenin induces apoptosis in a Comprehen-
sive panel of human cervical cancer-derived cell lines, Oxid. Med. Cell.
Longev. 2017 (2017) 1–18, https://doi.org/10.1155/2017/1512745.
 Y.-Y. Bao, S.-H. Zhou, J. Fan, Q.-Y. Wang, Anticancer mechanism of apigenin
and the implications of GLUT-1 expression in head and neck cancers, Futur.
Oncol. 9 (2013) 1353–1364, https://doi.org/10.2217/fon.13.84.
 K.K. Kumar, L. Priyanka, K. Gnananath, P.R. Babu, S. Sujatha, Pharmacoki-
netic drug interactions between apigenin, rutin and paclitaxel mediated by
P-glycoprotein in rats, Eur. J. Drug Metab. Pharmacokinet. 40 (2015) 267–276,
 S.-J. Choi, J.-S. Choi, The promotive effects of antioxidative apigenin on the
bioavailability of paclitaxel for oral delivery in rats, Biomol. Ther. 18 (2010)
 T. Lim, S. Park, J. Choi, Effects of apigenin, an antioxidant, on the bioavail-
ability and pharmacokinetics of etoposide, Korean J. Clin. Pharm. 21 (2011)
 Y. Chen, X. Jia, J. Chen, J. Wang, M. Hu, The pharmacokinetics of raloxifene
and its interaction with apigenin in rat, Molecules 15 (2010) 8478–8487, https:
 Y. Zhu, C. Liu, N. Nadiminty, W. Lou, R. Tummala, C.P. Evans, A.C. Gao, In-
hibition of ABCB1 expression overcomes acquired docetaxel resistance in
prostate cancer, Mol. Cancer Ther. 12 (2013) 1829–1836, https://doi.org/10.
 M. Saeed, O. Kadioglu, H. Khalid, Y. Sugimoto, T. Efferth, Activity of the di-
etary flavonoid, apigenin, against multidrug-resistant tumor cells as determined
by pharmacogenomics and molecular docking, J. Nutr. Biochem. 26 (2015)
 R.R. Ruela-de-Sousa, G.M. Fuhler, N. Blom, C. V Ferreira, H. Aoyama, M.P.
Peppelenbosch, Cytotoxicity of apigenin on leukemia cell lines: implications
for prevention and therapy, Cell Death Dis. 1 (2010) e19, https://doi.org/10.
 X. Liu, T. Xu, W. Li, J. Luo, P. Geng, L. Wang, M. Xia, M. Chen, L. Yu, G.-X.
Hu, The effect of apigenin on pharmacokinetics of imatinib and its metabolite
N-desmethyl imatinib in rats, Biomed. Res. Int. 2013 (2013)789184https://doi.