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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 potential 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 effects 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.
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Cancer Letters xxx (2017) xxx-xxx
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Cancer Letters
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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
Article history:
Received 9 August 2017
Received in revised form 25 October 2017
Accepted 26 October 2017
Available online xxx
Anticancer activity
Cell cycle arrest
Signalling pathways
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.
© 2017.
1. Introduction
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 [1]. 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 [2]. 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 [3]. 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 [4]. Interfering with the process
of carcinogenesis through diet or by the added digestion of natural
compounds has been termed “chemoprevention” [5]. An increasing
importance is being given today to alternative medicine and dietary
approach in prevention and treatment of cancer. A large number of
Corresponding author.
Email address: (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 [12].
The most extensively studied group of plant secondary metabo-
lites are polyphenols, characterized by their structure of multiple phe-
nol (benzene) rings [13]. 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
0304-3835/© 2017.
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
[14], 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 [13]. 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 [16] 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. [17] 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 [19]. 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 [20].
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
[21]. 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 [24], 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 [26]. 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 [27]. These spe-
cific properties categorise apigenin as part of a class of beneficial
compounds which possess health-promoting and disease-preventing
dietary effects.
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 [28]. A study by Chakrabarti et
al. [29] 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 [30]. 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 [31]. 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 [32].
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 [33]. 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 [34]. Recently, same authors evaluated the effect of apigenin in
combination with TRAIL on survival of ATC cells [35]. 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 [36].
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 [37]. 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 [38]. 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 [39]. 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 [40].
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. [41] 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 [42]. 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 [43].
Moreover, Kim et al. [44] 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 [45].
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 [46]. 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 [47].
The same group demonstrated that apigenin exposure led to p53-de-
pendent apoptosis in MDA MB-453 [48], SKBR3 [49] and BT-474
[50] 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-
ing BCC.
A study by Cao et al. [51] 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. [52] 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
α-tubulin [53].
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 [55]. 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. [56] 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 [57],
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) [59]. 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 [60].
A study by Shukla et al. [61] 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 [62]. 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 [63]. 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) [64].
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 [65].
Similarly, a study by Zhu et al. [66] 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
[67]. 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. [68]. 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 [69]. 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 [70].
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. [71] 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 [72]. 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 [73]. A recent
study by Wang and Zhao [74] 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 [75]. Interestingly, Banerjee and Mandal [76] 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
and HCT-15.
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 [77]. 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 [78].
Using an azoxymethane (AOM)-induced intestinal adenocarci-
noma in Wistar rat model, Tatsuta et al. [79] 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. [80] 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. [82] 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 [80], 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.
[83] 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 [84]. 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 [85]. 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 [86].
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 [87]. 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. [88] 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. [89]
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 [90]. 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 [91]. A study by Chao et al. [92] 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 [93]. 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 [94].
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 [95]. 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. [96] 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 [35]. 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 [97]. 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 [98]. Similarly, a study by Hu
et al. [99] 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
[100]. 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 [101].
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 [102]. More-
over, a recent study by Li et al. [103] 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 [104].
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 [105]. In a similar study, Tang et al.
[106] 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 [107]. 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 [108]. 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 [109]. 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 [86] 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 [99].
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 [110]. 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 [111], 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 [112]. 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) [113].
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 [114]. Saeed et al.
[115] 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. [116] 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 [117].
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
Table 1
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]
Bcl-xL [35,38,51,61,64,107]
Mcl-1 [32,73]
XIAP, cIAP-1 and -2 [61,87]
N-Myc [29,30]
Survivin [31,61,70]
Sharpin [70]
HDAC-1 and -3 [56,59,61]
hTERT [29,30]
GLUT-1 [41,42]
Her2/neu [46,47,54]
Axl, Tyro-3 [107]
GSH, SOD [90]
ΔΨM [38,74,76,78,90,99,108]
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]
PARP-1 [33–35,47–51,54,61,75,88,90,91,95,97–99]
Cytochrome c[61,69,74,84,87,90]
miR-16 and -138 [31,40]
c-Myc [33,34]
Fas [33]
DR5 [60,74,98]
TNF-α [28,38,69]
TRAIL [28]
Calpain [30,31]
CHOP [74]
Smac [31]
Apaf-1 [70]
ROS [28,36,52,53,74,76,90,99,108]
catalase [108]
decreased expression and/or activity p62 [36]
increased expression and/or activity LC3-II [36,51,75]
Beclin-1 [36]
Nrf-2 [36]
HO-1 [36]
Cell cycle
decreased expression and/or activity pRb [76]
Cyclin A, B1, D1 and E [29,37,56,64,72,75,76,87]
CDK-1, -2, and -4 [29,37,56,75]
Cdc25C [36]
PCNA [29,30]
CK2α [89,105,106]
increased expression and/or activity p16, p21 and p27 [29,47,48,56,59,62,69,70,75,76,84]
p53 [32,70,75]
altered phosphorylation p53 [33,47,48,50]
MDM2 [47]
altered cellular location p53 [84]
Angiogenesis, metastasis and invasion
decreased expression and/or activity VEGF [30,45,46,48–50,64,65,92,93]
COX-2 [64]
MMP-2 and -9 [29,30,32,40,50,69,71,93,104]
HIF-1α [48–50]
b-FGF [30]
Snail, Slug [66,69,70,100]
Oct-3 and -4 [69]
Sox-2 [44]
Nanog [44,45]
Twist-1 [93]
Vimentin [66,100]
N-cadherin [93,100]
NEDD9 [77]
CD44, 105 and 133 [44,45]
fibronectin [93]
Integrin subunits [91]
increased expression and/or activity E-cadherin [30,66,93,100]
transgelin [71]
Claudin-3 [100]
Occludin [100]
keratin-8 [93]
Cancer Letters xxx (2017) xxx-xxx 9
Table 1 (Continued)
Mechanism Effect Targets References
altered phosphorylation Smad-2 and -3 [65]
altered cellular location Smad-2 and -3 [65]
Snail [100]
Signalling pathways modulated by apigenin activity
PI3K/Akt/FoxO [62]
Src/FAK/Akt [65]
NEDD9/Src/Akt [77]
β-AR/Src/FAK/ERK [85]
integrin/FAK/ERK [91]
PI3K/Akt [30,35,41,42,52,69–71,73,92,107]
Akt/P70S6K1/MMP [104]
NF-κB [30,63,64,69,70,88]
GSK-3β/NF-κB [87]
NF-κB/MMP [40]
NF-κB/Snail [100]
ERK/Mcl-1 [73]
Wnt/β-catenin/TCF/LEF [72]
c-Myc/p38/p53 [33]
MAPK/ERK [34,35,92,95]
c-Met/STAT3/Akt/ERK [44]
Her2/neu [46]
p53 [47]
JAK/STAT [47–50,55,93]
Akt/mTOR [95]
Table 2
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 [42]
1-30 μM [73,98] 20 mg/kg/w [77]
1-40 μM [47,56,59,61,105–107] 5 or 25 mg/kg/d [56]
3-50 μM [28,32,38,52,54,65,75,91] 25 mg/kg/t.i.w. [89]
10-60 μM [77] 15 or 30 mg/kg/d [88]
2-80 μM [33,35,51,66,67,72,88] 25 mg/kg/d [73]
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 [104]
10-200 μM [100] 150 mg/kg/d [93]
40-280 μM [95] 200 or 300 mg/kg/d [100]
/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.
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... Due to the heterogenicity and plasticity of melanoma tumorigenesis, the use of combined therapies is needed [11,12], and is becoming standard care for metastatic patients [13]. However, heavily impairing side effects and unacceptable toxicities in patient populations all weigh unfavourably on the efficacy of current treatments [14][15][16][17][18]. There is a clear need for a multitargeted approach that is not hindered by the contraindications of present single-drug options. ...
... Further treatment limitations notably include their high cost [96]. Close to 80% of the cost of melanoma treatment was spent on drug treatments alone [14]. Furthermore, the cost of treatment in Australia rises tenfold in individuals with Stage III/IV diagnoses [14]. ...
... Close to 80% of the cost of melanoma treatment was spent on drug treatments alone [14]. Furthermore, the cost of treatment in Australia rises tenfold in individuals with Stage III/IV diagnoses [14]. ...
Full-text available
Melanoma is deadly, physically impairing, and has ongoing treatment deficiencies. Current treatment regimens include surgery, targeted kinase inhibitors, immunotherapy, and combined approaches. Each of these treatments face pitfalls, with diminutive five-year survival in patients with advanced metastatic invasion of lymph and secondary organ tissues. Polyphenolic compounds, including cannabinoids, terpenoids, and flavonoids; both natural and synthetic, have emerging evidence of nutraceutical, cosmetic and pharmacological potential, including specific anti-cancer, anti-inflammatory, and palliative utility. Cannabis sativa is a wellspring of medicinal compounds whose direct and adjunctive application may offer considerable relief for melanoma suffers worldwide. This review aims to address the diverse applications of C. sativa’s biocompounds in the scope of melanoma and suggest it as a strong candidate for ongoing pharmacological evaluation.
... 438,439 Apigenin was shown to inhibit cancer growth, invasion, and migration, and induce apoptosis in different tumor models. 440,441 In a recent study, apigenin was found to suppress invasion, migration, and EMT of prostate cancer cells. 442 Similarly, apigenin was reported to inhibit EMT-induced metastasis of prostate cancer cells by blocking Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) which is a crucial modulator of tumor growth and metastasis. ...
Epithelial‐mesenchymal transition (EMT) is a complex process with a primordial role in cellular transformation whereby an epithelial cell transforms and acquires a mesenchymal phenotype. This transformation plays a pivotal role in tumor progression and self‐renewal, and exacerbates resistance to apoptosis and chemotherapy. EMT can be initiated and promoted by deregulated oncogenic signaling pathways, hypoxia, and cells in the tumor microenvironment, resulting in a loss‐of‐epithelial cell polarity, cell–cell adhesion, and enhanced invasive/migratory properties. Numerous transcriptional regulators, such as Snail, Slug, Twist, and ZEB1/ZEB2 induce EMT through the downregulation of epithelial markers and gainof‐expression of the mesenchymal markers. Additionally, signaling cascades such as Wnt/β‐catenin, Notch, Sonic hedgehog, nuclear factor kappa B, receptor tyrosine kinases, PI3K/AKT/mTOR, Hippo, and transforming growth factor‐β pathways regulate EMT whereas they are often deregulated in cancers leading to aberrant EMT. Furthermore, noncoding RNAs, tumor‐derived exosomes, and epigenetic alterations are also involved in the modulation of EMT. Therefore, the regulation of EMT is a vital strategy to control the aggressive metastatic characteristics of tumor cells. Despite the vast amount of preclinical data on EMT in cancer progression, there is a lack of clinical translation at the therapeutic level. In this review, we have discussed thoroughly the role of the aforementioned transcription factors, noncoding RNAs (microRNAs, long noncoding RNA, circular RNA), signaling pathways, epigenetic modifications, and tumor‐derived exosomes in the regulation of EMT in cancers. We have also emphasized the contribution of EMT to drug resistance and possible therapeutic interventions using plant‐derived natural products, their semi‐synthetic derivatives, and nanoformulations that are described as promising EMT blockers.
... Flavonoids are a family of natural phenolic compounds widely present in plants, fruits and vegetables; they are characterized by possessing a C6-C3-C6 carbon skeleton base. These natural compounds have emerged as important anticancer agents as it has already been reported that they possess several properties in this way, namely apoptosis induction, the reduction of oxidative stress, the inhibition of angiogenesis and an increased DNA repair process, among others [1][2][3]. Quercetin, the main flavonoid explored in therapeutic applications, has already been studied for different types of cancer, and a higher therapeutic effect for human papillomavirus (HPV)-related cancers due to E6 oncoprotein inhibition capacity has been reported [4][5][6][7]. HPV is a virus with a high capacity to induce proliferative lesions in the skin and internal mucosa, mainly associated with the development of cervical cancer, which are responsible for 79 to 100% of cases [8]. ...
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Quercetin is a natural flavonoid with high anticancer activity, especially for related-HPV cancers such as cervical cancer. However, quercetin exhibits a reduced aqueous solubility and stability, resulting in a low bioavailability that limits its therapeutic use. In this study, chitosan/sulfonyl-ether-β-cyclodextrin (SBE-β-CD)-conjugated delivery systems have been explored in order to increase quercetin loading capacity, carriage, solubility and consequently bioavailability in cervical cancer cells. SBE-β-CD/quercetin inclusion complexes were tested as well as chitosan/SBE-β-CD/quercetin-conjugated delivery systems, using two types of chitosan differing in molecular weight. Regarding characterization studies, HMW chitosan/SBE-β-CD/quercetin formulations have demonstrated the best results, which are obtaining nanoparticle sizes of 272.07 ± 2.87 nm, a polydispersity index (PdI) of 0.287 ± 0.011, a zeta potential of +38.0 ± 1.34 mV and an encapsulation efficiency of approximately 99.9%. In vitro release studies were also performed for 5 kDa chitosan formulations, indicating a quercetin release of 9.6% and 57.53% at pH 7.4 and 5.8, respectively. IC50 values on HeLa cells indicated an increased cytotoxic effect with HMW chitosan/SBE-β-CD/quercetin delivery systems (43.55 μM), suggesting a remarkable improvement of quercetin bioavailability.
... In cell signaling pathways, some flavonoids can bind to protein kinases and alter their phosphorylation, such as MAP kinases. Myricetin, quercetin, (RSVL, a phytoalexin polyphenol), daidzein (equol), and delphinidin all can bind to MEK1 and inhibit the kinase activity without competing with ATP [22][23][24][25][26]. The first specific MEK1/2 inhibitor to be discovered was PD-098059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one], which is a flavone [27]. ...
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The second leading cause of death in the world is cancer. Mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinase (ERK) 1 and 2 (MEK1/2) stand out among the different anticancer therapeutic targets. Many MEK1/2 inhibitors are approved and widely used as anticancer drugs. The class of natural compounds known as flavonoids is well-known for their therapeutic potential. In this study, we focus on discovering novel inhibitors of MEK2 from flavonoids using virtual screening, molecular docking analyses, pharmacokinetic prediction, and molecular dynamics (MD) simulations. A library of drug-like flavonoids containing 1289 chemical compounds prepared in-house was screened against the MEK2 allosteric site using molecular docking. The ten highest-scoring compounds based on docking binding affinity (highest score: −11.3 kcal/mol) were selected for further analysis. Lipinski's rule of five was used to test their drug-likeness, followed by ADMET predictions to study their pharmacokinetic properties. The stability of the best-docked flavonoid complex with MEK2 was examined for a 150 ns MD simulation. The proposed flavonoids are suggested as potential inhibitors of MEK2 and drug candidates for cancer therapy.
... Cancer is a complex disease defined by uncontrolled cell growth, mutations, perturbed signalling cascades and metabolism, eventually escaping immune responses. This impairment leads to disturbed cellular growth, proliferation, angiogenesis, metastasis, and disabling of apoptosis and cell cycle checkpoint mechanisms, affecting the immune dynamics, and therefore is considered one of the leading factors for mortality and morbidity worldwide [1,2]. Studies related to immune cell responses and their interactions with tumours and perturbed signalling dynamics have been a centre of various theoretical and mathematical research. ...
Cancer therapy has been at the centre stage for decades in the scientific fraternity. Several chemical and biochemical actives have been studied for their effect on cancer therapy. In the present study, we have studied the therapeutic effects of a herbal formulation, Immusante, containing bioactive compounds such as Apigenin, Quercetin, Betulinic Acid, and Oleanolic Acid on cancer cell proliferation, angiogenesis and survival. The immunomodulatory effects of Immusante were incorporated in a cancer-specific mathematical model to quantify the therapeutic effects. Cancer model simulation with Immusante showed a significant reduction of tumour proliferation, reduction of immunosuppressive species, and increase in the CD8 effector T cell function. The effect of the Immusante, along with a chemotherapy drug, 5-fluorouracil (5-FU), was simulated to assess the effect of combination therapy. The addition of 5-FU as a monotherapy showed a 28% increase in the population with no/ very low tumorigenesis. A combination of 5-FU and Immusante showed a 44% increase in the population with no/very low tumorigenesis. A similar trend was seen for population size with low immune suppression, where 5-FU monotherapy showed a 26% increase, Immusante showed 12%, and a combination of 5-FU and Immusante showed a 43% increase in the population with low immune suppression, indicating increased efficiency of effector species in the presence of Immusante. Similar results were obtained for other drugs such as Cyclophosphamide, Platinum-based drugs, Vincristine, Taxane, Irinotecan, and Anthracyclines combined with Immusante. It is observed that chemotherapy alone can bring clearance in the tumour, further augmented by incorporating Immusante as a herbal adjuvant. Simulations suggest that combination enhances effectiveness and reduces the side effects of chemotherapy. It was observed that Immusante could effectively counter side-effects and adaptive response of cancer cells to improve efficacy and normalize immune response. The immunomodulatory properties of Immusante have been shown to restore balance in immune response and reduce the cytotoxic effects of drugs on healthy organs. These characteristics make Immusante a promising adjuvant during cancer management and improve the quality of the treatment.
... Furthermore, an animal model revealed that the mechanism involved reactive oxygen speciesand endoplasmic reticulum stress-dependent pathways that induced apoptosis [17]. The cytotoxic activity of apigenin (a flavone) has also been shown to involve free radical scavenging and promoting metal chelation in an in vivo tumor model [18]. In addition, it increased the glutathione concentration and enhanced endogenous defenses against oxidative stress [15]. ...
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In this study, we examined the cytotoxic activity of Eriocaulon cinereum R.Br. against breast cancer T47D cells and normal Vero cells. The plant material of E. cinereum was extracted with n-hexane followed by a series of extraction with ethyl acetate and finally with methanol. The ethyl acetate extract was then fractionated with dichloromethane and ethyl acetate. The dichloromethane fraction was concentrated, then fractionate using a preparative TLC. The subfractions obtained probably contained terpenoids (SF1), flavonoids (SF2), and steroids (SF3) as the three major compounds based on staining reagent and MS identifications. Later, the subfractions; SF1-SF3 were subjected to cytotoxic activity on breast cancer T47D cells. The result showed that the IC50 values against T47D cells are 84.8 ± 7.8, 89.7 ± 3.4, and 135 ± 12 μg/mL, respectively. In contrast, IC50 values against Vero cells were > 300 µg/mL for all compounds. Among them, the SF1 subfraction shown the good cytotoxic activity compared to other subfractions and has the potential to be further developed.
Introduction: Flavonoids are active substances in many herbal medicines, and Areca catechu fruit (AF), an important component in traditional Chinese medicine (TCM), is rich in flavonoids. Different parts of AF, Pericarpium Arecae (PA) and Semen Arecae (SA), have different medicinal effects in prescription of TCM. Objective: To understand flavonoid biosynthesis and regulation in AF. Methodology: The metabolomic based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the transcriptome based on high-throughput sequencing technology were combined to comprehensively analyse PA and SA. Results: From the metabolite dataset, we found that 148 flavonoids showed significant differences between PA and SA. From the transcriptomic dataset, we identified 30 genes related to the flavonoid biosynthesis pathway which were differentially expressed genes in PA and SA. The genes encoding the key enzymes in the flavonoid biosynthesis pathway, chalcone synthase and chalcone isomerase (AcCHS4/6/7 and AcCHI1/2/3), were significantly higher expressed in SA than in PA, reflecting the high flavonoid concentration in SA. Conclusions: Taken together, our research acquired the key genes, including AcCHS4/6/7 and AcCHI1/2/3, which regulated the accumulation of flavonol in AF. This new evidence may reveal different medicinal effects of PA and SA. This study lays a foundation for investigating the biosynthesis and regulation of flavonoid biosynthesis in areca and provides the reference for the production and consumption of betel nut.
Apigenin is a natural flavonoid which is widely found in vegetables and fruits. However, the mechanism of apigenin in oxidative stress-induced myocardial injury has not been fully elucidated. We established an isoproterenol (Iso)-induced myocardial injury mouse model and a hypoxia/reoxygenation (H/R)-induced H9c2 cell injury model, followed by pretreatment with apigenin to explore its protective effects. Apigenin can significantly alleviate isoproterenol-induced oxidative stress, cell apoptosis and myocardial remodeling in vivo. Apigenin pretreatment can also significantly improve cardiomyocyte morphology, decrease H/R induced oxidative stress, and attenuate cell apoptosis and inflammation in vitro. Further mechanism study revealed that apigenin treatment reversed isoprenaline and H/R-induced decrease of Sirtuin1 (SIRT1). Molecular docking results proved that apigenin can form hydrogen bond with 230 Glu, a key site of SIRT1 activation, indicating that apigenin is an agonist of SIRT1. Moreover, SIRT1 knockdown by siRNA significantly reversed the protective effect of apigenin in H/R-induced myocardial injury. In conclusion, apigenin protects cardiomyocyte function from oxidative stress-induced myocardial injury by modulating SIRT1 signaling pathway, which provides a new potential therapeutic natural compound for the clinical treatment of cardiovascular diseases.
Cancer is a complicated malignancy controlled by numerous intrinsic and extrinsic pathways. There has been a significant increase in interest in recent years in the elucidation of cancer treatments based on natural extracts that have fewer side effects. Numerous natural product‐derived chemicals have been investigated for their anticancer effects in the search for an efficient chemotherapeutic method. Therefore, the rationale behind this review is to provide a detailed insights about the anticancerous potential of apigenin via modulating numerous cell signaling pathways. An ingestible plant derived flavonoid called apigenin has been linked to numerous anticancerous potential in numerous experimental and biological studies. Apigenin has been reported to induce cell growth arrest and apoptotic induction by modulating multiple cell signaling pathways in a wider range of human tumors including those of the breast, lung, liver, skin, blood, colon, prostate, pancreatic, cervical, oral, and stomach. Oncogenic protein networks, abnormal cell signaling, and modulation of the apoptotic machinery are only a few examples of diverse molecular interactions and processes that have not yet been thoroughly addressed by scientific research. Thus, keeping this fact in mind, we tried to focus our review towards summarizing the apigenin‐mediated modulation of oncogenic pathways in various malignancies that can be further utilized to develop a potent therapeutic alternative for the treatment of various cancers. Apigenin‐mediated modulation of oncogenic pathways in various malignancies that can further aid in the elucidation of potent therapeutic alternative for cancer treatment.
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Pancreatic cancer (PC) evades immune destruction by favoring the development of regulatory T cells (Tregs) that inhibit effector T cells. The transcription factor Ikaros is critical for lymphocyte development, especially T cells. We have previously shown that downregulation of Ikaros occurs as a result of its protein degradation by the ubiquitin-proteasome system in our Panc02 tumor-bearing (TB) mouse model. Mechanistically, we observed a deregulation in the balance between Casein Kinase II (CK2) and protein phosphatase 1 (PP1), which suggested that increased CK2 activity is responsible for regulating Ikaros’ stability in our model. We also showed that this loss of Ikaros expression is associated with a significant decrease in CD4⁺ and CD8⁺ T cell percentages but increased CD4⁺CD25⁺ Tregs in TB mice. In this study, we evaluated the effects of the dietary flavonoid apigenin (API), on Ikaros expression and T cell immune responses. Treatment of splenocytes from naïve mice with (API) stabilized Ikaros expression and prevented Ikaros downregulation in the presence of murine Panc02 cells in vitro, similar to the proteasome inhibitor MG132. In vivo treatment of TB mice with apigenin (TB-API) improved survival, reduced tumor weights and prevented splenomegaly. API treatment also restored protein expression of some Ikaros isoforms, which may be attributed to its moderate inhibition of CK2 activity from splenocytes of TB-API mice. This partial restoration of Ikaros expression was accompanied by a significant increase in CD4⁺ and CD8⁺ T cell percentages and a reduction in Treg percentages in TB-API mice. In addition, CD8⁺ T cells from TB-API mice produced more IFN-γ and their splenocytes were better able to prime allogeneic CD8⁺ T cell responses compared to TB mice. These results provide further evidence that Ikaros is regulated by CK2 in our pancreatic cancer model. More importantly, our findings suggest that API may be a possible therapeutic agent for stabilizing Ikaros expression and function to maintain T cell homeostasis in murine PC.
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Recently, the cytotoxic effects of apigenin (4′,5,7-trihydroxyflavone), particularly its marked inhibition of cancer cell viability both in vitro and in vivo, have attracted the attention of the anticancer drug discovery field. Despite this, there are few studies of apigenin in cervical cancer, and these studies have mostly been conducted using HeLa cells. To evaluate the possibility of apigenin as a new therapeutic candidate for cervical cancer, we evaluated its cytotoxic effects in a comprehensive panel of human cervical cancer-derived cell lines including HeLa (human papillomavirus/HPV 18-positive), SiHa (HPV 16-positive), CaSki (HPV 16 and HPV 18-positive), and C33A (HPV-negative) cells in comparison to a nontumorigenic spontaneously immortalized human epithelial cell line (HaCaT). Our results demonstrated that apigenin had a selective cytotoxic effect and could induce apoptosis in all cervical cancer cell lines which were positively marked with Annexin V, but not in HaCaT (control cells). Additionally, apigenin was able to induce mitochondrial redox impairment, once it increased ROS levels and H 2 O 2 , decreased the Δψm , and increased LPO. Still, apigenin was able to inhibit migration and invasion of cancer cells. Thus, apigenin appears to be a promising new candidate as an anticancer drug for cervical cancer induced by different HPV genotypes.
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Apigenin (4′,5,7-trihydroxyflavone) is a flavonoid commonly found in many fruits and vegetables such as parsley, chamomile, celery, and kumquats. In the last few decades, recognition of apigenin as a cancer chemopreventive agent has increased. Significant progress has been made in studying the chemopreventive aspects of apigenin both in vitro and in vivo. Several studies have demonstrated that the anticarcinogenic properties of apigenin occur through regulation of cellular response to oxidative stress and DNA damage, suppression of inflammation and angiogenesis, retardation of cell proliferation, and induction of autophagy and apoptosis. One of the most well-recognized mechanisms of apigenin is the capability to promote cell cycle arrest and induction of apoptosis through the p53-related pathway. A further role of apigenin in chemoprevention is the induction of autophagy in several human cancer cell lines. In this review, we discuss the details of apigenin, apoptosis, autophagy, and the role of apigenin in cancer chemoprevention via the induction of apoptosis and autophagy.
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Cancer is a serious concern at present. A large number of patients die each year due to cancer illnesses in spite of several interventions available. Development of an effective and side effects lacking anticancer therapy is the trending research direction in healthcare pharmacy. Chemical entities present in plants proved to be very potential in this regard. Bioactive phytochemicals are preferential as they pretend differentially on cancer cells only, without altering normal cells. Carcinogenesis is a complex process and includes multiple signaling events. Phytochemicals are pleiotropic in their function and target these events in multiple manners; hence they are most suitable candidate for anticancer drug development. Efforts are in progress to develop lead candidates from phytochemicals those can block or retard the growth of cancer without any side effect. Several phytochemicals manifest anticancer function in vitro and in vivo. This article deals with these lead phytomolecules with their action mechanisms on nuclear and cellular factors involved in carcinogenesis. Additionally, druggability parameters and clinical development of anticancer phytomolecules have also been discussed.
The aim of this study was to evaluate the inhibiting effect of apigenin on liver cancer in vivo based on the optical molecular imaging method. Subcutaneous liver tumor models were established using respective 1 × 10⁶ firefly luciferase (fLuc) and green fluorescent protein (GFP) labeled human hepatocellular carcinoma cells (HepG2-fLuc and HepG2-GFP cells) in 20 BALB/c nude mice which were randomly divided into two groups, 10 in each group. After the tumor cells were implanted 15 days, apigenin was administered through intraperitoneal injection in group B, the other ten mice as control group A. Bioluminescence imaging (BLI) and fluorescence molecular imaging (FMI) were carried out for the follow-up of subcutaneous tumor model. As time goes on, intensity and distribution of bioluminescence and fluorescence of tumours increased gradually with the growth of tumours little by little. The whole process of observation was in accordance with known activities of HCC in the human liver. The tumor volume and tumor weight were significant lower in group B than in group A (p < 0.05), Subcutaneous tumours in the apigenin treatment group B based on BLI and FMI were significantly inhibited compared to the control group A (p < 0.05). Apigenin could be expected as a new drug to treat hepatocellular carcinoma. Optical molecular imaging technology enabled the non-invasive and reliable assessment of anti-tumor drug efficacy on liver cancer.
Malignant melanoma is the most invasive and fatal form of cutaneous cancer. Moreover it is extremely resistant to conventional chemotherapy and radiotherapy. Apigenin, a non-mutagenic flavonoid, has been found to exhibit chemopreventive and/or anticancerogenic properties in many different types of human cancer cells. Therefore, apigenin may have particular relevance for development as a chemotherapeutic agent for cancer treatment. In the present study, we investigated the effects of apigenin on the viability, migration and invasion potential, dendrite morphology, cell cycle distribution, apoptosis, phosphorylation of the extracellular signal-regulated protein kinase (ERK) and the AKT/mTOR signaling pathway in human melanoma A375 and C8161 cell lines in vitro. Apigenin effectively suppressed the proliferation of melanoma cells in vitro. Moreover, it inhibited cell migration and invasion, lengthened the dendrites, and induced G2/M phase arrest and apoptosis. Furthermore, apigenin promoted the activation of cleaved caspase-3 and cleaved PARP proteins and decreased the expression of phosphorylated (p)‑ERK1/2 proteins, p-AKT and p-mTOR. Consequently, apigenin is a novel therapeutic candidate for melanoma.
Recent endeavors in exploiting vast array of natural phytochemicals to ameliorate colorectal cancer led us to investigate apigenin, a naturally occurring dietary flavone as a potential chemo-therapeutic agent. The present study focuses on establishing apigenin as a potential chemotherapeutic agent for alleviating colorectal cancer and reports the development of a stable liposomal nanocarrier with high encapsulation of the hydrophobic flavone apigenin for enhanced chemotherapeutic effects. The enhanced pharmacological activity of apigenin has been assigned to its ability to interact and subsequently influence membrane properties which also resulted in optimal yield of a stable, rigidified, non-leaky nano-carrier with ideal release kinetics. Extensive testing of drug and its liposomal counterpart for potential clinical chemotherapeutic applications yielded hemocompatibility and cytocompatibility with normal fibroblast cells while enhanced antineoplastic activity was observed in tumor xenograft model. The increased chemotherapeutic potential of liposomal apigenin highlights the clinical potential of apigenin-based vesicles.
Apigenin is one of the plant-originated flavones with anticancer activities. In this study, apigenin was assessed for its in vitro effects on a human colon carcinoma line (HCT‑116 cells) in terms of anti-proliferation, cell cycle progression arrest, apoptosis and intracellular reactive oxygen species (ROS) generation, and then outlined its possible apoptotic mechanism for the cells. Apigenin exerted cytotoxic effect on the cells via inhibiting cell growth in a dose-time-dependent manner and causing morphological changes, arrested cell cycle progression at G0/G1 phase, and decreased mitochondrial membrane potential of the treated cells. Apigenin increased respective ROS generation and Ca2+ release and thereby, caused ER stress in the treated cells. Apigenin shows apoptosis induction towards the cells, resulting in enhanced portion of apoptotic cells. A mechanism involved ROS generation and endoplasmic reticulum stress was outlined for the apigenin-mediated apoptosis via both intrinsic mitochondrial and extrinsic pathways, based on the assayed mRNA and protein expression levels in the cells. With this mechanism, apigenin resulted in the HCT-116 cells with enhanced intracellular ROS generation and Ca2+ release together with damaged mitochondrial membrane, and upregulated protein expression of CHOP, DR5, cleaved BID, Bax, cytochrome c, cleaved caspase-3, cleaved caspase-8 and cleaved caspase-9, which triggered apoptosis of the cells.
Objective: Cancer stem cells contribute to tumor recurrence, and a hypoxic environment is critical for maintaining cancer stem cells. Apigenin is a natural product with anticancer activity. However, the effect of apigenin on cancer stem cells remains unclear. Our aim was to investigate the effect of apigenin on cancer stem cell marker expression in head and neck squamous cell carcinoma cells under hypoxia. Design: We used three head and neck squamous cell carcinoma cell lines; HN-8, HN-30, and HSC-3. The mRNA expression of cancer stem cell markers was determined by semiquantitative RT-PCR and Real-time PCR. The cytotoxic effect of apigenin was determined by MTT colorimetric assay. Flow cytometry was used to reveal the number of cells expressing cancer stem cell surface markers. Results: HN-30 cells, a cancer cell line from the pharynx, showed the greatest response to hypoxia by increasing their expression of CD44, CD105, NANOG, OCT-4, REX-1, and VEGF. Apigenin significantly decreased HN-30 cell viability in dose- and time-dependent manners. In addition, 40μM apigenin significantly down-regulated the mRNA expression of CD44, NANOG, and CD105. Consistent with these results, the hypoxia-induced increase in CD44(+) cells, CD105(+) cells, and STRO-1(+) cells was significantly abolished by apigenin. Conclusion: Apigenin suppresses cancer stem cell marker expression and the number of cells expressing cell surface markers under hypoxia.