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Current Organic Chemistry, 2019, 23, 2945-2959 2945
MINI-REVIEW ARTICLE
1385-2728/19 $58.00+.00 © 2019 Bentham Science Publishers
Anticancer Activity of Natural Flavonoids: Inhibition of HIF-1α Signaling Pathway
Xiangping Deng1, Yijiao Peng1, Jingduo Zhao1, Xiaoyong Lei1, Xing Zheng1, Zhizhong Xie1 and Guotao
Tang1,*
1Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study,
University of South China, Hengyang, P.R. China
A R T I C L E H I S T O R Y
Received: October 10, 2019
Revised: November 02, 2019
Accepted: November 20, 2019
DOI:
10.2174/1385272823666191203122030
Abstract: Rapid tumor growth is dependent on the capability of tumor blood vessels and
glycolysis to provide oxygen and nutrients. Tumor hypoxia is a common characteristic of
many solid tumors, and it essentially happens when the growth of the tumor exceeds the
concomitant angiogenesis. Hypoxia-inducible factor 1 (HIF-1) as the critical transcription
factor in hypoxia regulation is activated to adapt to this hypoxia situation. Flavonoids,
widely distributed in plants, comprise many polyphenolic secondary metabolites, possess-
ing broadspectrum pharmacological activities, including their potentiality as anticancer
agents. Due to their low toxicity, intense efforts have been made for investigating natural
flavonoids and their derivatives that can be used as HIF-1α inhibitors for cancer therapy
during the past few decades. In this review, we sum up the findings concerning the inhibi-
tion of HI F-1α by natural flavonoids in the last few years and propose the idea of designing tumor vascular and
glycolytic multi-target inhibitors with HIF-1α as on e of the targets.
Keywords: HIF-1α, natural flavonoids, anticancer, inhibition, signaling pathway, hypoxia situation.
1. INTRODUCTION
Tumor hypoxia is a common characteristic of many solid tu-
mors, and it essentially happens when the growth of the tumor ex-
ceeds the concomitant angiogenesis [1, 2]. Therefore, it is not sur-
prising that many parts of developing tumor are hypoxic and ne-
crotic [3]. Hypoxia-inducible factor 1 (HIF-1) is the critical tran-
scription factor in the regulation of hypoxia. HIF-1 is closely re-
lated to the occurren ce and development of tumors, such as angio-
genesis, glycolysis, metastasis, cell survival and apoptosis [4-8].
HIF-1 is a heterodimer composed of two subunits: HIF-1α, an oxy-
gen-regulated protein, and HIF-1β that is constitutively expressed.
HIF-1α subunit is degraded fleetly in normoxic conditions and sta-
bilized under hypoxic conditions, while HIF-1β is constantly ex-
pressed as a nuclear protein. HIF-1 activity in tumors depends on
the availability of the HIF-1α subunit, the levels of which increase
under hypoxic conditions and through activation of oncogenes
and/or inactivation of tumor suppressor genes [9-12]. The prolyl
hydroxylation of HIF-1α at the oxygen-dependent degradation do-
main (ODD) is pivotal in the regulation of HIF-1α steady-state
levels. Under normoxic conditions, the proline residue on the HIF-
1α is hydroxylated, promoting the degradation of the HIF-1α. This
hydroxylation process is mediated by prolyl hydroxylase (PHD), a
series of enzymes that are dependent on oxygen, iron ions o r ascor-
bic acid and a dioxygenase superfamily of ketoglutarate. Von Hip-
pel Lindau (VHL) tumor suppressor protein facilitates the hydroxy-
lation of the HIF-1α and degrades the HIF-1α in a ubiquitinated
*Address correspondence to this author at the Guotao Tang, Institute of Pharmacy and
Pharmacology, University of South China, Hengyang, Hunan, 421001, P.R. China;
E-mail: tgtzq@163.com
form. Under hypoxic conditions, the velocity of hydroxylation and
ubiquitination descends, leading to the accumulation of HIF-1α.
HIF-1α enters the nucleus and dimerizes with HIF-1β to form a
HIF-1 transcription factor. Within the nucleus, HIF-1 binds to the
A/GCGTG sequence on the promoter region of the target gene, the
hypoxia response element (HRE), to initiate gene transcription
(Fig. 1) [13-17]. An increasing number of anticancer agents such as
flavonoids have been shown to inhibit HIF-1 activity. For many of
them, the mechanism of action has been ful ly established and in-
volves signaling pathways linked to HIF-1 mRNA expression, HIF-
1 protein translation, HIF-1 protein degradation or HIF-1 transcrip-
tional activity/DNA binding [10]. Considering that HIF-1α is over-
expressed in a majority of human cancers, natural flavonoids are
promising anticancer therapeutic agents targeting HIF-1α.
Hypoxia, CoCl2-, H2O2- or IGF-treatment can increase HIF-1α
levels. Moreover, in many cancers, growth factors, cytokines and
other signaling molecules stimulate HIF-1α synthesis by activating
the phosphatidylinositol 3 -kinase (PI3K) or mitogen-activated pro-
tein kinase (MAPK) pathways. mTOR activity is an important de-
terminant of the rate of HIF-1α protein synthesis. The constitutive
activation of receptor tyrosine kinases (such as HER2neu, BCR-
ABL, and EGFR) and/or the downstream PI3K/AKT and
RAS/MAP kinase signal transduction pathways in cancer cells lead
to increased mTOR activity and the induction of HIF-1 activity.
MAPK pathways involved in HIF-1α regulation results in the acti-
vation of ERK1-2 (also called p44/42) after activation of the up-
stream molecules Ras/Raf/MEK-1/ERK1-2. Furthermore, the chap-
erone HSP90 interacts with HIF-1α and is required for HIF-1 tran-
scriptional activity and HIF -1 protein stability [10, 11]. In addition
to some of the common and important signaling molecules men-
Guotao Tang
2946 Current Organic Chemistry, 2019, Vol. 23, No. 26 Deng et al.
tioned above, there are many signaling pathways involved in the
regulation of HIF-1.
Flavonoids are a series of compounds in which two benzene
rings (A- and B-ring s) are linked via a central 3-carbon bridge,
forming a C6-C3-C6 system. The skeleton of flavonoids consists of
2-phenyl-4H-chromen-4-one (Fig. 2). Flavonoids belong to a kind
of secondary metabolites with a wide distribution in nature. Over
5000 naturally occurring flavonoids have been characterized by
various plants. Flavonoids have been classified according to their
chemical structure and are usu ally subdivided into several sub-
groups, including anthoxanthins, flavanones, flavanonols, flavans,
anthocyanidins and iso flavonoids (Table 1) [18-21]. They are one
of the main active ingredients in medicinal plants and have a wide
range of pharmacological activities, such as anti-inflammatory ac-
tivity [22-26], antioxidant activity [27, 28], antiviral activity [29,
30], antibacterial activity [31-33], anti-platelet aggregation effects
[34, 35], cardiovascular disease protection [26, 36] and so on. Due
to their great anti-tumor potential, flavonoids have drawn a lot of
attention in the development of anticancer drugs [26, 37-40]. It has
been reported that flavonoids have anticancer and preventive effects
against several common human cancer such as stomach, prostate,
colon, breast, lung and ovarian cancers [41-45]. Flavonoids exert
their anticancer activity with different and multiple signal transduc-
tion pathways [36, 45, 46]. So far, accumulating evidence concerns
flavonoids as HIF-1 inhibitors for drug therapy [47, 48]. In the past
decade, several studies have summarized the anticancer activity and
structure-activity relationship of natural flavonoids, but few reviews
have outlined the role of natural flavonoids on HIF-1. In this re-
view, we hope to provide a more comprehensive overview of the
inhib ition of flavonoids on HIF -1 (Tables 2-7) to provide researchers
with a thought to design potent and low-toxic anticancer drug candi-
dates.
O
O
1
2
3
4
5
6
7
81'
2'
3'
4'
5'
6'
A
B
C
Fig. (2). The basic core structure of flavonoids.
2. ANTHOXANTHINS
Anthoxanthins, including flavones and flavonols, are a type of
flavonoid pigments in plants. Chrysin (5,7-Dihydroxy-2-phenyl-
4H-chromen-4-one) reduces the stability of HIF-1α by increasing
prolyl hydroxylation of the ODD, resulting in inhibiting insulin-
induced expression of HIF-1α in human prostate cancer DU145
cells [49]. Binding of HIF-1α to Hsp90 prevents HIF-1α degrada-
tion. Moreover, the expression of HIF-1α is inhibited by chrysin
through interfering with the interaction between HIF-1α and heat
shock protein 90 (Hsp90) but also the AKT signaling pathway [49].
Baicalein (Fig. 3) (5,6,7-Trihydroxy-2-phenyl-chromen-4-one) is
originally isolated from the roots of Scutellaria baicalensis and
Scutellaria lateriflora. Baicalein inhibited the cell viability of two
kinds of human ovarian cancer (OVCAR-3 and A2780/CP-70) cell
Fig. (1). Regulation of HIF-1α activity under normoxia and hypoxia. ADM: adrenomedullin; EG-VEGF: endocrine-gland-derived vascular endothelial growth
factor; GLUT: Glucose transporter; HK: Hexokinase; HRE: hypoxia response element; LDHA: lactate dehydrogenase A; LOX: lysyl oxidase; MET: Met
proto-oncogene/hepatocyte growth factor receptor; MMP-2, MMP-9 and MMP-14: matrix metalloproteinase 2, 9 and 14; OCT4: octamer binding protein 4;
PDK1: pyruvate dehydrogenase kinase 1 ; PFKL: 6-phosphofructokinase, liver type; PGM: phosphoglycerate mutase; PHD: prolyl hydroxylase; Pr: Proline;
TERT: telomerase; TGFA: transforming growth factor α; TGF-β3: transforming growth factor beta-3; Ub: ubiquitin; VEGF: vascular endothelial growth fac-
tor; VEGFR: vascular endothelial growth factor receptor; VHL: von Hippel Lindau tumor suppressor protein.
Anticance r Activity of Natural Fla vonoid s Current Organic Chem istry, 2019, Vol. 23 , No. 26 2947
Table 1. Classification of flavonoids.
Group
Structural Fo rmula
Description
Examples
Flavone
O
O
2-phen ylchrom en-4-one
Chrysin , Baicalein, Apigenin, Luteo-
lin, Wogonin, Acacetin, Vitexin
Anthoxanthins
Flavonol
O
O
OH
3-hydro xy-2-phenylchromen-4-one
Galangin, Kaempferol,
Fisetin, Querc etin, Myri cetin,
Isorhamnetin, Rutin
Flavanones
Flavanone
O
O
2,3-dihydro-2-phenylchromen-4-one
Liquiritigenin, Naringin, Blumeatin,
Butin, Er iodictyol, Hesperetin
Flavanonols
Flavanonol
O
O
OH
3-hydro xy-2,3-dihydro-2-
phenylchromen-4-one
Taxifolin, Aromadedrin
Flavan-3-ol
O
OH
2-phen yl-3,4-dihydro-2H-chromen-3-ol
Epigallocatechin, Epigallocatechin
gallate, Proanthocyanidin, Theafla-
vin digallate
Flavan-4-ol
O
OH
2-phen yl-3,4-dihydro-2H-chromen-4-ol
Apiforol, Luteoforol
Flavans
Flavan-3,4-diol
O
OH
OH
2-phen yl-3,4-dihydro-2H-chromen-3,4-
diol
Leucocyanidin, Leucodelphinidin,
Leucofisetinidin, Leucomalvidin
Anthocyanidins
Anthocyanidin
O
2-phen ylchrom enylium ion
Delphinidin, Cyanidin, Aurantin idin,
Europinidin
Isoflavonoids
Isoflavanes
Isoflavenes
isoflavonones
rotenoids
Pterocarpans
O
O
3-phen ylchrom en-4-one
Daidzein, Genistein, Biochan in A,
Alpinumisoflavone, Deguelin
2948 Current Organic Chemistry, 2019, Vol. 23, No. 26 Deng et al.
lines in a concentration-dependent manner (LD50=39.4 µM for
OVCAR-3 at 24 h, LD50=24.3 µM for A2780/CP70 at 24 h), while
exhibited lower cytotoxicity in normal ovarian cell line IOSE-364
(LD50=68 µM), suggesting that baicalein had a certain extent of
selectivity to human ovarian cancer cells. The potential mech anism
for inhibition of human ovarian cancer cell viability by baicalein
treatment is the suppression of the cancer-promoting genes expres-
sion including HIF-1α [50]. Baicalein (IC50=78.0 µM at 48 h) at the
concentration of 50 µM inhibits HIF-1α stabilization and also sup-
presses its transcription activity in human breast cancer MCF-7
cells in vitro [51]. Baicalein also suppresses hypoxia-enhanced
glycolytic flux and the key glycolysis-associated enzymes (HK2,
LDH-A and PDK1) in the human gastric adenocarcinoma AGS
cells, and reduces HIF -1α expression via inhibiting hypoxia-
induced Akt phosphorylation. Baicalein also is found to suppress
hypoxia-induced Akt phosphorylation through the promotion of
PTEN (an upstream negative regulator of Akt) accumulation in
AGS cells, suggesting that baicalein may inhibit hypoxia-dependent
HIF-1α expression via the PTEN/Akt pathway. The research dem-
onstrates that baicalein reverses hypoxia-induced 5-FU resistance
through the suppression of glycolysis via regulation of th e
PTEN/Akt/HIF-α signaling pathway [52]. The in vivo, treatment
with baicalein (20 and 40 mg/kg/day, i.p.) has been found to sig-
nificantly suppress the intracerebral tumor growth and lengthen the
survival in the U87 orthotopic glioma models. Moreover, treatment
with baicalein decreased the expression of HIF-1α in U87 gliomas
[53]. Apigenin (Fig. 3) (5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-
benzopyran-4-one), a natural product belonging to the flavone
class, significantly down-regulates the expression of HIF-1α mRNA
at the concentration of 50 µM in human pancreatic cancer CD18
and S2-013 cells in both normoxic and hypoxic conditions [54].
Apigenin has also been found to inhibit HIF-1α expression via in-
terfering with th e binding of HIF-1α and Hsp90 in human hepatoma
Hep3B cells, leading to the reduction of VEGF expression. In addi-
tion, apigenin degrades HIF-1α via a pVHL-independent pathway
[55, 56]. Importantly, apigenin significantly suppresses tumor angi-
ogenesis in vivo in human prostate carcinoma PC-3 cells and human
ovarian cancer cells OVCAR-3 cells which are linked to the de-
crease of HIF-1 and VEGF, via using the chicken chorioallantoic
membrane (CAM), Matrigel plug assays and immunoblotting [56].
GSK-3b is a well-characterized downstream substrate of Akt. Inhi-
bition of HIF-1α by apigenin treatment in human prostate carci-
noma PC3-M cells is accompanied by the phosphorylation (activa-
tion) of Akt and phosphorylation (inhib ition) of GSK -3b, suggest-
ing the involvement of PI3K/Akt/GSK-3 pathway in HIF-1 inhibi-
tion [57]. p70S6K1 is a downstream target of PI3K/AKT. p53 func-
tions to promote the degradation of HIF-1. HDM2 is the protein
that mediates p53 degradation by binding p53 and stimulating the
addition of ubiquitin to the carboxyl terminus of p53 for degrada-
tion.Inhibition of AKT activation impaired the HDM2 phosphoryla-
tion leading to its destabilization and degradation, which accounts
for the induction of the p53 protein. Apigenin also inhibits HIF-1
expression via PI3K/Akt/p70S6K1 and HDM2/p53 pathways in
human ovarian cancer cells OVCAR-3 and A2780/CP70 [58].
Luteolin (Fig. 3) (2-(3,4-Dihydroxyphenyl)- 5,7-dihydroxy-4-
chromenone) has a strong antican cer effect and its mechanism is
associated with the inhibition of HIF-1α in mouse macrophage
RAW264.7 cells under hypoxic conditions [59]. IC50 values of lute-
olin after 24, 48 and 78 h of incubation were 140.73, 64.94, and
44.45 µM for A375 cells and 143.89, 67.34, and 55.09 µM for B16-
F10 cells, respectively. Luteolin shows anti-metastasis activity by
reducing the p-Akt, HIF-1α, VEGF-A, p-VEGFR-2, MMP-2, and
MMP-9 proteins expression in human A375 melanoma cells and
mouse B16-F10 melanoma cells [60]. Treatment of luteolin plus
radiation reduces the expression levels of VEGF and HIF-1α in the
gastric cancer cell line SGC-7901 [61]. Luteolin reduces HIF-1α
nuclear accumulation in human cervical carcinoma (HeLa) cells,
and also inhibits HIF-1α phosphorylation and its transcriptional
activity via interfering with the MAPK pathway. Wogonin (Fig. 3)
(5,7-Dihydroxy-8-methoxy-2-phenyl-4H-chromen-4-one) is a fla-
vone with a remarkable antitumor activity. Wogonin has anti-
proliferative activity against SGC-7901 and A549 cells by a time-
and concentration-dependent manner. The inhibitory rates of SGC-
7901 and A549 cells following wogonin treatment (15 µg/mL) were
35.00±0.12 and 54.17±0.24%, respectively. Wogonin has the inhi-
bition effect of the energy metabolism, cell proliferation and angio-
genesis in SGC-7901 and human carcinoma A549 cells via decreas-
ing HIF-1α protein expression [62]. Wogonin can induce the activa-
tion of caspase-3 by inhibiting the expression of HIF-1α and sur-
vivin in human eosinophilic leukemia EoL-1 cells, thereby promot-
ing cell apoptosis [63]. Wogonin can repress H IF-1α expression and
glycolysis by suppressing PI3K/Akt signaling pathway in human
colon cancer HCT116 cells in vitro and vivo, which may be the
potential mechanism of the reversion of wogonin resistance [64].
Proto-oncogene c-Myc enforces cellular proliferation and growth in
tumors [11] and cooperates with HIF-1 in inducing VEGF expres-
sion. As c-Myc/HIF-1α signaling axis is reported to play a critical
role in angiogenesis via controlling VEGF expression and secretion,
treatment by wogonin increases HIF-1α-VHL interaction, and pro-
motes HIF-1α degradation through proteasome/ubiquitinatio n
pathway without affecting HIF-1α mRNA expression level. It has
been found that the inhibition of multiple myeloma-stimulated
angiogenesis and tumor progression by wogonin in the human mul-
tiple myeloma cell lines RPMI 8226 is associated with
c-Myc/VHL/HIF-1α signaling axis [65]. Acacetin (Fig. 3) (5,7-
dihydroxy-2-(4-methoxyphenyl)-4H-chromen-4-one)is a flavone
compound and has anti-cancer activity. Acacetin promotes the deg-
radation of HIF-1α protein and decreases the stability of HIF-1α
protein, resulting in the attenuation of HIF-1α expression. In addi-
tion , acacetin inhibits HIF-1α expression and AKT activation to
restrain VEGF expression, thereby significantly suppressing
OVCAR-3 cell-induced angiogenesis and tumor growth in vivo
[66]. Vitexin (Fig. 3) (5, 7, 4-trihydroxyflavone-8-glucoside) as an
HIF-1α inhibitor reduces the mRNA level of transcriptional genes
(VEGF, etc.) controlled by HIF-1α [67, 68], and inhibits the protein
levels HIF-1α in rat pheochromocytoma (PC12) [67]. Vitexin re-
duced HIF-1α expression in MCF-7 cells [69]. Baicalin (Fig. 3)
((2S,3S,4S,5R, 6S)-6-(5,6-dihydroxy-4-oxo-2-phenyl-chromen-7-
yl)oxy-3,4,5-trihydroxy-tetrahydropyran-2-carboxylic acid) is the
glucuronide of baicalein. LD50 is calculated for two cancer cell lines
and the normal ovarian cell line: 44.6 µM for OVCAR-3, 55.2 µM
for A2780/CP70, and 177.0 µM for IOSE-364 treated by baicalin.
Baicalin exerts antiproliferative activities in human lung carcinoma
A549 cell line and mouse Lewis lung cancer (LLC) cell line by a
concentration- and time-dependent manner [70]. It has been re-
ported that baicalin enhances SOD activity and decreases HIF-1α
stabilization to suppress cancer cell proliferation and metastasis
[70-72].
Flavonols are a class of flavonoids that have the 3-
hydroxyflavone backbone. Galangin (Fig. 4) (3,5,7-Trihydroxy-2-
phenyl-chromen-4-one), a flavonol, down-regulates the level
of HIF-1α protein in A2780/CP70 and OVCAR-3 cells [73]. The
Anticance r Activity of Natural Fla vonoid s Current Organic Chem istry, 2019, Vol. 23 , No. 26 2949
O
O
HO
OH
Chrysin
O
O
HO
OH
Baicalein
HO
O
O
HO
OH
Apigenin
O
O
HO
OH
Luteolin
O
O
HO
OH
Wogonin
O
O
HO
OH
Acacetin
OH
OH
OCH3
OH
OCH3
O
O
O
O
HO
OH OH
OH
HO
O
HO
OH
HO OH
O
OH
OH
OH
HO
O
Vitexin Baicalin
Fig. (3). The structure of flavones inhibiting HIF-1α signaling pathway.
Table 2. Natural flavones that affect HIF-1α signaling pathway and function.
Compounds
Target
Mechanism of HIF-1 Inhibition
Cancer Cell Line
Reference
Chrysin
ODD
HIF-1α stabilization
DU145 cells
[49]
Hsp90 and AKT signaling pathway
HIF-1α expression
DU145 cells
[49]
Baicalein
Akt phosphorylation and PTEN/Akt
pathway
HIF-1α expression
OVCAR-3cells ; A2780/CP-
70 cells ; AGS cells; U87
cells
[50,52,53]
HIF-1α stabilization and transcription
activity
MCF-7 cells
[51]
Apigenin
Hsp90 or PI3K/Akt/GSK-3,
PI3K/Akt/p70S6K1 and HDM2/p53
pathways
HIF-1α expression
Hep3B cells; PC-3 cells;
PC3-M cells; OVCAR-3
cells; A2780/CP70 cells
[55-58]
HIF-1α mRNA level
CD18 cel ls; S2-013 cells
[54]
HIF-1α degradation
Hep3B cells
[55]
Luteolin
HIF-1α expression
RAW264.7 cell; A375 cells;
B16-F10 ce lls; SGC-7901
cells
[59-61]
MAPK pathway
HIF-1α phosphorylation and its transcrip-
tional activity
HeLa cells
[70]
Wogonin
PI3K/Akt signaling pathway
HIF-1α expression
SGC-7901 cells; A549 cells;
EoL-1 cells; HCT116 cells
[62-64]
proteasome/ubiquitination pathway
HIF-1α degradation
RPMI 8226 cells
[65]
Acacetin
HIF-1α degradation and HIF-1α stabiliza-
tion
OVCAR-3 cell
[66]
Vitexin
HIF-1α expression
PC12 cells; MCF-7 cells
[67-69]
Baicalin
HIF-1α stabilization
A549 cell; LLC cells
[70-72]
dietary flavonol kaempferol (Fig. 4) (3,5,7-trihydroxy-2-(4-
hydroxyphenyl)-4H-1-benzopyran-4-one) has been shown to inhibit
HIF-1 activity concentration-dependently with an IC50 value of 5.16
µM on human hepatoma (Huh7) cancer cells under hypoxic condi-
tions (1% oxygen). The mechanism is involved in the mislocaliza-
tion of HIF-1 into the cytoplasm caused by the inactivation of
2950 Current Organic Chemistry, 2019, Vol. 23, No. 26 Deng et al.
p44/42 MAPK by kaempferol (IC50=4.75 µM) [74]. Treatment of
two ovarian cancer cells (OVCAR-3 and A2780/CP70) with
kaempferol down-regulates the expression of HIF-1α and inhibits
AKT phosphorylation in a concentration-dependent manner at 5 to
20 µM concentrations. Kaempferol is shown to repress angiogene-
sis and VEGF expression on human ovarian cancer cells via HIF-
dependent (Akt/HIF) and HIF-independent (ESRRA, estrogen-
related receptor alpha) signaling path [75]. Quercetin (Fig. 4) (2-
(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chrom en-4-one), a
plant flavonol, attenuates the activity of HIF-1 and suppresses tu-
mor growth in an HCT116 cancer xenograft mod el [76]. Compared
with doxorubicin alone, treatment combined with doxorubicin and
quercetin (0.7 µM) significantly represses cell proliferation and
invasion on MCF-7 and MCF-7/dox cells and inhibits HIF-1α and
permeability glycoprotein (P-gp) expression [77]. Under normoxic
conditions, a slight effect of treatment with quercetin on cell viabil-
ity and DOX-induced cytotoxicity is observed in 4T1 breast cancer
cells. Conversely, quercetin protects spleen cells from DOX-
induced toxic side effects in vitro under hypoxic conditions. Quer-
cetin inhibits HIF-1α in tumors in a hypoxia-dependent manner,
while increases its accumulation in normal cells. These results sug-
gest that quercetin can enhance the treatment index of DOX
through its opposite effect on HIF-1α in normal cells and tumors
[78]. Quercetin inhibits the accumulation of HIF-1α by suppression
of protein synthesis in a concentration-dependent manner under
hypoxic conditions on human prostate cancer LNCaP, colon cancer
CX-1, and breast cancer SkBr3 cells [79]. Quercetin also signifi-
cantly represses the transcriptional activation of HIF-1 by hypoxia
in the RIF cell line (derived from a radiation-induced fibrosarcoma)
[80]. Quercetin down-regulates the expression of HIF-1α in human
neuroblastoma SK-N-MC cell line resulting in the decrease of
Foxo3a and Notch intracellular domain (NICD) contents, accompa-
nying up-regulation of p53 and Bax as pro-apoptotic factors, and
further to cause cell death induced by oxidative stress [81].
Myricetin (Fig. 4) (3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)-4-
chromenone) has demonstrated potent anti-neoplastic properties
[82, 83]. Myricetin suppresses the expression of UVB-induced HIF-
1α in an SKH-1 hairless mouse skin tumorigenesis model [84].
Myricetin down-regulates the level of HIF-1α and represses the
expression of VEGF by th e Akt/p70S6K/ HIF-1α and p21/HIF-
1α/VEGF pathway in OVCAR-3 cells [73]. Isorhamnetin (Fig. 4)
(3,5,7-trihydroxy-2-(4-hydroxy-3-methoxyphenyl) chromen-4-one),
a flavonol metabolite of quercetin, markedly inhibits CoCl2-, H2O2-
or hypoxia-induced HIF-1α accumulation in colorectal cancer cells
(HCT116 and HT29). Isorhamnetin has been found to be a better
inhibitor of HIF-1 than quercetin [85].
3. FLAVANONES
Liquiritigenin (Fig. 5) ((2S)-7-Hydroxy-2-(4-hydroxyphenyl)-
2,3-dihy-dro-4H-chromen-4-one) is a dietary flav anone with vari-
ous anti-cancer activities. Liquiritigenin could block its kinase ac-
tivity in breast cancer cells (MCF-7 and MDA-MB-231) via pro-
moting HIF-1α proteasome degradation and directly interacting
with VEGFR-2, thereby remarkably inhibiting the VEGF expres-
sion [86]. Liquiritigenin significantly represses both serum - and
mimicked hypoxia-induced HIF-1α protein accumulation but does
not affect the HIF-1α mRNA level. Moreover, liquiritigenin de-
creases the stability and synthesis of HIF-1α to suppress serum-
induced HIF-1α expression in a concentration-dependent manner.
Mechanistically, liquiritigenin inhibits serum-induced HIF-1α and
VEGF expression in HeLa cells and the mechanisms correlate with
the AKT/mTOR-p70S6K signaling pathway [87]. Naringin (Fig. 5)
(7-[[2-O-(6-Deoxy-α-L-mannopyranosyl)-β-D-glucopyranosyl]ox-
y]-2,3-dihydro-5-hydro-xy-2-(4-hydroxyphenyl)-4H-1-benzopyran
-4-one) is a flavanone-7-O-glycoside and shows its antitumor ef-
fects [88, 89] via regulating cell cycle progression, promoting tu-
mor cell apoptosis, repressing angiogenesis, and inhibiting metasta-
sis and invasion. Naringin suppresses the expression of HIF-1α on
human melanoma cell line A375 and A875 cells [90].
4. FLAVANS
The flavans are benzopyran derivatives with the 2-phenyl-3,4-
dihydro-2H-chromene skeleton, including the flavan-3-ols, flavan-
O
O
OH
HO O
O
OH
HO O
O
OH
HO
O
O
OH
HO O
O
OH
HO
OH
OH
OCH3
OH
OH
OH
OH
Myricetin Isorhamnetin
Quercetin
Galangin Kaempferol
OH
OH
OH
OH
OH
OH
Fig. (4). The structure of flavonols inhibiting HIF-1α signaling pathway.
Anticance r Activity of Natural Fla vonoid s Current Organic Chem istry, 2019, Vol. 23 , No. 26 2951
Table 3. Natural flavonols that affect HIF-1α signaling pathway and function.
Compounds
Target
Mechanism of HIF-1 Inhibition
Cancer Cell Line
reference
Galangin
HIF-1α expression
A2780/CP70 cells;
OVCAR-3 cells
[73]
Kaempferol
p44/42 MAPK pathway
HIF-1 activity
Huh7 cells
[74]
AKT phosphorylation
HIF-1α expression
OVCAR-3cells;
A2780/CP70 cells
[75]
Quercetin
HIF-1 activity
HCT116 cells
[76]
HIF-1α expression
4T1 cells; SK-N-MC cells
[77,78,81]
protein synthesis
HIF-1α accumulation
LNCaP cells; CX-1 cells;
SkBr3 cells
[79]
HIF-1 transcription activity
RIF cells
[80]
Myricetin
Akt/p70S6K/ HIF-1α and p21/HIF-
1α/VEGF pathways
HIF-1α expression
OVCAR-3 cells; SKH-1
hairless mouse skin tu-
morigenesis model
[73,84]
Isorhamnetin
HIF-1α accumulation
HCT116 cells; HT29 cells
[85]
O
O
HO
OH
O
O
O
OH
O
O
O
OH
HO
HO
HO
H3C
OHOH
OH
Liquiritigenin Naringin
Fig. (5). The structure of flavanones inhibiting HIF-1α signaling pathway.
Table 4. Natural flavanones that affect HIF-1α signaling pathway and function.
Compounds
Target
Mechanism of HIF-1 Inhibition
Cancer Cell Line
Reference
Liquiritigenin
HIF-1α proteasome
HIF-1α expression
MDA-MB-231 cells
[86]
AKT/mTOR-p70S6K pathways
HIF-1α accumulation, the stability and
synthesis of HIF-1α
HeLa cells
[87]
Naringin
HIF-1α expression
A375 cells; A875 cells
[90]
4-ols and flavan-3,4-diols (leucoanthocyanidin). Epigallocatechin
(Fig. 6) (5,7-triol,3,4-dihydro-2-(3,4,5-trihydroxyphenyl)-2H-
1-benzo-pyran-(2r-cis)) is a flavan-3-ol. Epigallocatechin as a
critical compound for LDH-A-inhibition activity of spatholobus
suberectus suppresses lactate dehydrogenase A (LDH-A) activity in
MCF-7 and MDA-MB-231 cells, owing to the disassociation of
Hsp90 from HIF-1α and subsequent accelerated HIF-1α proteasome
degradation. Epigallocatechin can significantly suppress the growth
of breast cancer and the expression of HIF-1α/LDH-A, and induce
apoptosis with no toxic effects [91]. Epigallocatechin gallate
(EGCG) ([(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chro-
man-3-yl]3,4,5-trihydroxybenzoate), also called as epigalloc-
atechin-3-gallate, is the ester of epigallocatechin and gallic acid,
and is a type of catechin. EGCG inhibits cell growth and prolifera-
tion ag ainst breast cancer cells MCF-7, possibly due to the suppres-
sion of the HIF-1α and VEGF protein expression [92]. Addition-
ally, EGCG is found to observably inhibit the HIF-1α protein ex-
pression upregulated by IGF-I induction in A549 cells. EGCG re-
presses IGF-I-stimulated lung cancer angiogenesis via down-
regulating HIF-1α and VEGF expression [93]. HIF-1α-dependent
angiogenesis in vitro and in vivo is promoted by overexpression of
human papillomavirus (HPV)-16 E6 and E7 oncoproteins, which is
repressed by EGCG. Mechanistically, EGCG suppresses HPV-16
oncoprotein-induced HIF-1α protein expression while it does not
affect HIF-1α mRNA expression in non-small cell lung cancer
(NSCLC) cells (A549 and NCI-H460). Meanwhile, EGCG sup-
presses HIF-1α-dependent activation of Akt mediated by HPV-16
oncoproteins in A549 cells. Moreover, HPV-16 oncoprotein-
induced HIF-1α and HIF-1α-dependent VEGF and CD31 expres-
sions are suppressed by EGCG in A549 xenografted tumors [94].
2952 Current Organic Chemistry, 2019, Vol. 23, No. 26 Deng et al.
Treatment of human cervical carcinoma cells C-33A with EGCG
significantly represses th e HPV-16 oncoproteins-induced expres-
sion of HIF -1α, and VEGF protein and mRNA concentration-
dependently [95]. In the human pancreatic carcinoma cell line
PANC-1, EGCG inhibits the expression of the HIF-1α protein in a
concentration-dependent manner under hypoxic conditions but has
no effects on HIF-1α mRNA [96]. EGCG suppresses the accumula-
tion of HIF-1α protein in HeLa and hepatoma (HepG2) cells while
having no effects on HIF-1α mRNA expression, probably due to the
blocking of both PI3K/Akt and extracellular signal-regulated kinase
(ERKs) 1/2 signaling pathways and the acceleration of HIF-1α
protein degradation [97]. Chemically, proanthocyanidin (Fig. 6)
(2-(3,4-Dihydroxyphenyl)-2-((2-(3,4-dihydroxyphenyl)-3,4-dihy-
dro-5,7-di-hydroxy-2H-1-benzopyran-3-yl)oxy)-3,4-dihydro-2H-
1-benzopyr-an-3,4,5,7-tetrol) is oligomeric flavonoids, constituted
by oligomers of catechin and epicatechin and their gallic acid esters
or forming the group of tannins via the same polymeric building
block. Grape seed extract-standardized preparation, comprising at
least 85% (wt/wt) proanthocyanidin, decreases HIF-1α protein syn-
thesis by inhibiting Akt activation in human glioma U251 cells or
human breast cancer MDA-MB-231 cells [98]. Theaflavin digallate
(Fig. 6) ([1-[(2R,3R)-3,5-Dihydroxy-7-(3,4,5-trihydroxybenzoyl)
oxychroman-2-yl]-3,5-dihydroxy-6-oxo-8-[(3R)-3,5,7-trihydroxy-
chroman -2-yl] benzo[7]annulen-4-yl] 3,4,5-trihydroxybenzoate),
also known as theaflavin-3, 3'-digallate, is a theaflavin derivative
found in black tea. Theaflavin digallate is demonstrated to inhibi t
human ovarian carcinoma OVCAR-3 cell-induced tumor angio-
genesis by down-regulating HIF-1α and VEGF and is more effec-
tive than EGCG. The involved mechanism is that theaflavin di-
gallate inhibits activation of the Akt and Notch-1 pathway [99].
5. ANTHOCYANIDINS
Anthocyanidins are common plant pigments. They are the
sugar-free counterparts of anthocyanins based on the flavylium ion
or 2-phenylchromenylium, which is a type of oxonium ion
(chromenylium is also referred to as benzopyrylium). Delphinidin
(Fig. 7) (also named as delphinidin) (2-(3,4,5-Trihydroxyphenyl)
chromenylium-3,5,7-triol) is a kind of an anthocyanidin and pos-
sesses anti-proliferative, and anticancer activities against many
cancer cells [100-102]. Delphinidin specifically down-regulates the
expression of CoCl2- and epidermal growth factor (EGF)-induced
HIF-1α protein in A549 cells through inhibiting th e PI3K/
Akt/mTOR/p70S6K and ERK signaling pathways [103]. Besid es,
delphinidin modulates the intracellular level of Cdk inhibitor
(CDKI) protein p27 via modulating HIF-1 level and PI3K/
Akt/mTOR signaling pathway [104].
6. ISOFLAVONOIDS
Isoflavone is a type of naturally occurring isoflavonoids. Soy-
beans are the most common source of isoflavones in human food
and the major isoflavones in soybean are daidzein and genistein.
Daidzein (Fig. 8) (7-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-
one) and genistein (Fig. 8) (5,7-Dihydroxy-3-(4-hydroxy-
O
OH
OH
OH
OH
OH
HO
O
OH
OH
OH
OH
HO
O
OOH
OH
OH
O
O
HO
HO
O
OH
OH
OH
HO
OH
OH
OH
OH
O
OH
HO
O
O
HO
OH
OH
O
HO
OH
HO
O
OH
OH
OO
OH
OH
HO
Epigallocatechin Epigallocatechin gallate
Proanthocyanidin Theaflavin digallate
Fig. (6). The structure of flavans inhibiting HIF-1α signaling path way.
Anticance r Activity of Natural Fla vonoid s Current Organic Chem istry, 2019, Vol. 23 , No. 26 2953
phenyl)chromen-4-one), are known isoflavones that are described
as radiosensitizers for prostat e cancer [105-108]. Daidzein sup-
presses cell growth and enhances radiation in vitro, and inhibits the
expression of HIF-1α in PC-3 and C4-2B cells. Compared with
daidzein, genistein is more potent [105]. However, daidzein does
not promote metastasis to lymph nodes and guards against genis-
tein-induced metastasis [105, 107]. The expression levels of HIF-1α
and VEGF protein in SW480 cell s were markedly lower in the
normoxia group (P < 0.01, P < 0.05, respectively) and hy-
poxia/genistein group (P < 0.01, P < 0.05, respectively) than in the
hypoxia group, suggesting that genistein inhibits the expression of
hypoxia-induced HIF-1α [109, 110]. Genistein decreases the ex-
pression of VEGF mRNA by inhibiting the DNA-binding activity
of HIF-1 in human pancreatic carcinoma cell lines Capan-1 and
Mia PaCa-2 [111]. Genistein can inhibit CoCl2-induced HIF-1α
expression in a concentration-dependent manner in K562 cells but
has no effect on HIF-1α mRNA [112]. Genistein induces mitochon-
drial apoptosis through directly down-regulating HIF-1α protein in
aerobic g lycolytic hepatocellular carcinoma (HCC) cells, thereb y
inactivating GLUT1 and HK2 for inhibiting aerobic glycoly sis
[113]. Genistein as an inhibitor of tyrosine kinases can completely
inhibit the synthesis of HIF-1 subunits and HIF-1 DNA-binding
activity in Hep3B cells [114]. Biochanin A (Fig. 8) (5,7-Dihydroxy-
3-(4-methoxyphenyl)chromen-4-one) is classified as an isoflavone
known for its potential anticancer activity. Biochanin A inhibits the
expression of CoCl2-induced HIF-1α and VEGF in rat brain tumor
C6 cells, which contributes to the inhibition of angiogen esis [115].
Alpinumisoflavone (Fig. 8) (5-hydroxy-3-(4-hydroxyphenyl)-8,8-
dimethylpyrano[3,2-g]chromen-4-one), a pyranoisoflavone, inhibits
hypoxia-induced HIF-1 activation with IC50 values of 5 µm in hu-
man breast tumor T47D cells [116]. Deguelin (Fig. 8) ((7aS,13aS)-
13,13a-Dihydro-9,10-dimethoxy-3,3-dimethyl-3H-bis [1]benzopy-
rano[3,4-b:6’,5’-3]pyran-7(7aH)-one) is a derivative of rotenone
which belongs to isoflavonoid. Deguelin exhibits inhibitory effects
on the HIF transcriptional activity and the HIF-1α expression by
blocking protein synthesis and by inducing the ubiquitin-mediated
proteasome degradation pathway in H1299 lung cancer cells [117,
118]. Further evidence indicates that deguelin only marginally in-
hibits HIF-1 mRNA expression, whereas significantly inhibits the
expression of HIF-1α protein in H1299 cells under normoxic IGF-
stimulated and hypoxic conditions which is independent of ROS,
PHD, pVHL and PI3K-Akt pathways. Moreover, Hsp90 is involved
in the deguelin-mediated HIF-1α ubiquitination and destabilization.
[119]. Furthermore, HIF-1α degradation was found to be correlated
with Hsp90 binding. Inhibition of Hsp90 function by deguelin in-
hibits the increase in HIF-1α/Hsp90 interaction and HIF-1α expres-
sion in the radioresistant lung cancer cells (H1299, H226B,
H226Br, and H460) [120].
CONCLUSION AND FUTURE PERSPECTIVES
It is worth noting that global cancer mortality has not declined
over the past few decades in spite of new anticancer drugs and more
sensitive means for early detection of malignancies. Thus, there is
an urgent need for discovering new and rel iable anticancer drugs to
improve the survival rates of cancer patients. Rapid tumor growth is
dependent on the capability of tumor blood vessels and glycolysis
O
OH
OH
OH
OH
OH
HO
Delphinidin
Fig. (7). The structure of anthocyanidins inhibiting HIF-1α signaling path-
way.
Table 5. Natural flavans that affect HIF-1α signaling pathway and function.
Compounds
Target
Mechanism of HIF-1 Inhibition
Cancer Cell Line
Reference
Epigallocatechin
HIF-1α expression
MCF-7 cells; MDA-MB-
231 cells
[91]
Epigallocatechin gallate
Akt
HIF-1α expression
MCF-7 cells;
A549 cells;
C-33A cells; PANC-1 cells
[92-96]
PI3K/Akt and ERKs 1/2 signalin g
pathways
HIF-1α accumulation
HeLa cells; HepG2 cells
[97]
Proanthocyanidin
Akt activation
HIF-1α protein synthesis
U251 cells; MDA-MB-231
cells
[98]
Theaflavin digallate
Akt activation and Notch-1 path-
way
HIF-1α expression
OVCAR-3 cells
[99]
Table 6. Natural anthocyanidins that affect HIF-1α signaling pathway and function.
Compounds
Target
Mechanism of HIF-1 Inhibition
Cancer Cell Line
Reference
Delphinidin
PI3K/Akt/mTOR/p70S6K and ERK
signaling pathways
HIF-1α expression
A549 cells
[103, 104]
2954 Current Organic Chemistry, 2019, Vol. 23, No. 26 Deng et al.
O
O
HO
OH
O
O
HO
OH
O
O
HO
OCH3
OH OH
O
O
OH
O
OH
O
O
O
O
O
O
H
H
Daidzein Genistein Biochanin A
Alpinumisoflavone Deguelin
Fig. (8). The structure of isoflavonoids inhibiting HIF-1α signaling pathway.
Table 7. Natural isoflavonoids that affect HIF-1α signaling pathway and function.
Compounds
Target
Mechanism of HIF-1 Inhibition
Cancer Cell Line
Reference
Daidzein
HIF-1α expression
PC-3 cells; C4-2B cells
[105]
Genistein
HIF-1α expression
SW480 cells; K56 2 cells;
PC-3 cells; C4-2B cells;
HCC cells
[109, 110, 112, 105,
113]
HIF-1 subunits synthesis and HI F-1
DNA-binding activity
Capan-1 cells; Mia PaCa-2
cell; Hep3B cells
[111, 114]
Biochan in A
HIF-1α expression
C6 cells
[115]
Alpinumisoflavone
HIF-1 activation
T47D cells
[116]
Deguelin
protein synthesis and the ubiquitin-
mediated proteasome degradation
pathway
the HIF transcriptio nal activity and
the HIF-1α expression
H1299 cells
[117]
Hsp90
HIF-1α protein expression, HIF-1α
ubiquitination and destabilization
H1299 cells
[119]
PI3K/Akt/mTOR-mediated de novo
protein synthesis
HIF-1α/Hsp90 interaction and HIF-1α
expression
H1299 cells; H226B cells;
H226Br cells; H460 cells
[120]
to provide oxygen and nutrients. Moreover, the discrepancy be-
tween the swift rate of tumor growth and the ability of established
blood vessels to provide oxygen and nutrients make the adaptation
to hypoxia environment the foundation for the survival and growth
of tumor cells [48, 121, 122]. Most flavonoids have an inhibitory
effect on HIF -1α, and a few have stable and induced HIF-1α ef-
fects. The m ain objective of this review is focused on the inhibitio n
of HIF-1α by natural flavonoids. HIF-1α plays an important role in
hypoxia regulation as well as in cancer development. Fig. (9) repre-
sents the HIF-1α signaling pathway involved in the inhibition of
tumor vasculature, glycolysis and metastasis by natural flavonoids.
Interestingly, in addition to the inhibition of tumor angiogenesis
and glycolysis by inhibiting HIF-1α, flavonoids also block the es-
tablished tumor vascular [123]. Herein, our research group has p ro-
posed an idea of whether the flavonoids can be structurally modi-
fied to simultaneously inhibit tumor blood vessels and glycolysis,
completely severing the source of oxygen and nutrients of tumor
cells. Currently, a pharmacophore combination approach has been
proposed to design new anti-tumor molecules that act synchro-
nously on more than one target by combining two/more active
pharmacophores covalently in a single-hybrid molecule with
dual/multiple anti-tumor functions [124-126]. Moreover, most natu-
ral flavonoids have th e disadvantages of poor fat solubility or poor
water solubility, low bioavailability, and poor stability. The natural
flavonoids can be structurally modified to improve the solubility of
flavonoids and enhance physiological activity and stability. Our
Anticance r Activity of Natural Fla vonoid s Current Organic Chem istry, 2019, Vol. 23 , No. 26 2955
group introduced amino acids or amino groups into the flavonoid
structure to improve water solubility and bioavailability. Th e phar-
macophore combination approach is feasible for the development of
flavonoids as multi-target inhibitors for cancer therapy. Under-
standing the effects of anti-cancer flavonoids on HIF-1α may be
useful for developing new compounds with enhanced anti-cancer
properties.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
Financial support from the Hunan Province Cooperative Inno-
vation Center for Molecular Target New Drug Study (0223-0002-
0002000-49) and Graduate student science foundation of the Uni-
versity of South China (2018479) are gratefully acknowledged.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or oth-
erwis e.
ACKNOWLEDGEMENTS
Declared none.
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