ArticlePDF AvailableLiterature Review

Genistein and Cancer: Current Status, Challenges, and Future Directions


Abstract and Figures

Primary prevention through lifestyle interventions is a cost-effective alternative for preventing a large burden of chronic and degenerative diseases, including cancer, which is one of the leading causes of morbidity and mortality worldwide. In the past decade, epidemiologic and preclinical evidence suggested that polyphenolic phytochemicals present in many plant foods possess chemopreventive properties against several cancer forms. Thus, there has been increasing interest in the potential cancer chemopreventive agents obtained from natural sources, such as polyphenols, that may represent a new, affordable approach to curb the increasing burden of cancer throughout the world. Several epidemiologic studies showed a relation between a soy-rich diet and cancer prevention, which was attributed to the presence of a phenolic compound, genistein, present in soy-based foods. Genistein acts as a chemotherapeutic agent against different types of cancer, mainly by altering apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. Targeting caspases, B cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2, kinesin-like protein 20A (KIF20A), extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear transcription factor κB (NF-κB), mitogen-activated protein kinase (MAPK), inhibitor of NF-κB (IκB), Wingless and integration 1 β-catenin (Wnt/β-catenin), and phosphoinositide 3 kinase/Akt (PI3K/Akt) signaling pathways may act as the molecular mechanisms of the anticancer, therapeutic effects of genistein. Genistein also shows synergistic behavior with well-known anticancer drugs, such as adriamycin, docetaxel, and tamoxifen, suggesting a potential role in combination therapy. This review critically analyzes the available literature on the therapeutic role of genistein on different types of cancer, focusing on its chemical features, plant food sources, bioavailability, and safety.
Content may be subject to copyright.
Genistein and Cancer: Current Status, Challenges,
and Future Directions
Carmela Spagnuolo,
Gian Luigi Russo,
* Ilkay Erdogan Orhan,
Solomon Habtemariam,
Maria Daglia,
Antoni Sureda,
Seyed Fazel Nabavi,
Kasi Pandima Devi,
Monica Rosa Loizzo,
Rosa Tundis,
and Seyed Mohammad Nabavi
Institute of Food Sciences, National Research Council, Avellino, Italy;
Department of Pharmacognosy, Faculty of Pharmacy, Gazi University,
Ankara, Turkey;
Pharmacognosy Research Laboratories, Medway School of Science, University of Greenwich, Chatham-Maritime, United
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Pavia, Italy;
Group on Community Nutrition and Oxidative Stress and CIBERobn (Physiopathology of Obesity and Nutrition), University of Balearic Islands,
Palma de Mallorca, Spain;
Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran;
Department of
Biotechnology, Alagappa University, Karaikudi, Tamil Nadu, India; and
Department of Pharmacy, Health, and Nutritional Sciences, University of
Calabria, Rende, Italy
Primary prevention through lifestyle interventions is a cost-effective alternative for preventing a large burden of chronic and degenerative
diseases, including cancer, which is one of the leading causes of morbidity and mortality worldwide. In the past decade, epidemiologic and
preclinical evidence suggested that polyphenolic phytochemicals present in many plant foods possess chemopreventive properties against
several cancer forms. Thus, there has been increasing interest in the potential cancer chemopreventive agents obtained from natural sources,
such as polyphenols, that may represent a new, affordable approach to curb the increasing burden of cancer throughout the world. Several
epidemiologic studies showed a relation between a soy-rich diet and cancer prevention, which was attributed to the presence of a phenolic
compound, genistein, present in soy-based foods. Genistein acts as a chemotherapeutic agent against different types of cancer, mainly by
altering apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. Targeting caspases, B cell lymphoma 2 (Bcl-2)associated X protein
(Bax), Bcl-2, kinesin-like protein 20A (KIF20A), extracellular signal-regulated kinase 1/2 (ERK1/2), nuclear transcription factor kB (NF-kB), mitogen-
activated protein kinase (MAPK), inhibitor of NF-kB(IkB), Wingless and integration 1 β-catenin (Wnt/β-catenin), and phosphoinositide 3 kinase/
Akt (PI3K/Akt) signaling pathways may act as the molecular mechanisms of the anticancer, therapeutic effects of genistein. Genistein also
shows synergistic behavior with well-known anticancer drugs, such as adriamycin, docetaxel, and tamoxifen, suggesting a potential role in
combination therapy. This review critically analyzes the available literature on the therapeutic role of genistein on different types of cancer,
focusing on its chemical features, plant food sources, bioavailability, and safety. Adv Nutr 2015;6:40819.
Keywords: genistein, cancer, source, bioavailability, safety
The International Agency for Research on Cancer, which is
part of the WHO, reported that of the estimated 14.1 million
adults worldwide who were diagnosed with cancer in 2012,
8.2 million deaths were recorded (1). Moreover, on the basis
of recent trends in the incidence of major cancers and pro-
jected population growth, >23 million new cancer cases an-
nually are expected by 2030. This means 68% more cases of
cancer than in 2012 (2). The most commonly diagnosed
cancer types worldwide are lung, breast, and colorectal,
whereas those with a higher index of mortality are lung,
liver, and stomach (3).
It is therefore necessary to have new, affordable ap-
proaches to curb the increasing burden of cancer through-
out the world (4). It is widely known that dietary habits have
cancers (58).
High intakes of animal fat, energy, and alcohol increase
the cancer risk (912), whereas foods of plant origin exert
their protective effects due to the presence of phytochemi-
cals via different mechanisms of action (i.e., antioxidant ca-
pacity, hormonal activity, stimulation of enzymes, interference
with DNA replication) (1318). These biological and functional
A Sureda was supported by CIBEROBN (CB12/03/30038).
Author disclosures: C Spagnuolo, GL Russo, IE Orhan, S Habtemariam, M Daglia, A Sureda,
SF Nabavi, KP Devi, MR Loizzo, R Tundis, and SM Nabavi, no conflicts of interest.
* To whom correspondence should be addressed. E-mail: (GL Russo), (SM Nabavi).
408 ã2015 American Society for Nutrition. Adv Nutr 2015;6:408–19; doi:10.3945/an.114.008052.
Downloaded from by guest on 02 December 2020
activities are ascribed both to the micronutrient content of plant
foods, such as vitamins and minerals, as well as plant secondary
metabolites, such as polyphenols, sulfur-containing compounds,
terpenes, and alkaloids (1925). Among them, the most studied
compounds are polyphenols, which have been investigated for
their potential protective effects on human health over the
past 2 decades (2629).
Polyphenols are generally subdivided into 2 large groups:
avonoids and nonavonoids (30). Isoavones are avonoids
in which the B ring is linked to the heterocyclic ring at the C3
instead of the C2 position (31, 32). The most important
isoavones are genistein and daidzein (Figure 1), followed
by glycitein, formononetin, and biochanin A (Figure 2),
which can occur in foods both in free and esterified forms
(glycosylated, acetyl- and malonyl-glycosylated forms) (33).
The intake of soy products has been attributed to the lower
incidence of breast and prostate cancer in Asian populations,
which is mainly due to the presence of an isoavone called
genistein. When compared with the other isoavones, genis-
tein was observed to have structural similarity to 17b-estradiol
and to possess weak estrogenic activity. It competes with 17b-
estradiol for the estrogen receptor (ER),
with 4% binding
affinity for ER-aand 87% for ER-b, thereby contributing a
favorable role in the treatment of hormone-related cancers
(34). Moreover, many in vitro and in vivo studies also support
that genistein can be considered a promising chemopreventive
agent for the treatment of different types of cancer. In this
article we review the beneficial role of genistein against differ-
ent types of cancer, which were selected among those that are
more common and with a high mortality rate. We also discuss
the chemistry, plant food sources, bioavailability, and safety of
genistein. Finally, we provide some recommendations that
could be useful in directing future studies on this isoflavone.
Genistein [49,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-
(4-hydroxyphenyl) chromen-4-one] (C
) belongs
to a multifunctional natural isoflavonoid class of flavonoids
with a 15-carbon skeleton. Similar to other plant constitu-
ents, such as lignans, which possess estrogenic effect, genis-
tein is a typical example of a phytoestrogenic compound. It
was isolated for the first time from Genista tinctoria L. in
1899 and named after the genus of this plant. Since then,
it has been found to occur as the main secondary metabolite
of the Trifolium species and in Glycine max L. (synonym Soja
hispida) (35). As shown in Figure 1, the chemical structure
of genistein is similar to estradiol, leading to its binding abil-
ity to ERs (3639). It possesses a high solubility in polar sol-
vents including dimethylsulfoxide, acetone, and ethanol,
although its solubility is much lower in water.
Although total organic synthesis of genistein was
achieved in 1928, it has also been obtained by using various
other methods. Chemical synthesis of genistein was per-
formed via cyclization of the corresponding ketones by us-
ing a conventional microwave oven (40). Biotechnological
synthesis of genistein was earlier reported to be achieved
through conversion of (2S)-naringen into genisteinin
NAD(P)H- and oxygen-dependent conditions as well as by
the addition of cytochrome P-450 (CYP) in elicitor-treated
soybean cell suspension cultures (41). Moreover, a metabolic-
engineering approach to genistein synthesis was set up
by using genetically engineered Saccharomyces cerevisiae
yeast cells that contained the isoflavone synthase (IFS)
gene isolated from Glycyrrhyza echinata L. (42). Similarly,
genistein was produced in Nicotiana tabacum L. leaves trans-
formed with IFS, by acting at the phenylpropanoid pathway, al-
though UV-B treatment also enhanced genistein production in
Arabidopsis (43).
On this basis and because of the known benecial biolog-
ical effects of genistein, chemists have been so far encouraged
to synthesize many derivatives of this compound, with im-
proved pharmacologic prole. For instance, FA-esteried
(44), 6-carboxymethyl (45), nitroxy (46), 7-O-heterocycle
(47), 7-O-b-D-glucoside (48) and 7-O-b-D-glucuronic acid
(49), halogenated (50, 51), deoxybenzoin (50), benzylated
(52), hydroxylated (53), esterified (54), benzosulfonate (55),
dimethylaminomethyl (56), phenoxyalkylcarboxylic acid
(57), glycoconjugate, and alkylbenzylamine (58) derivatives
of genistein have been reported to date. All of these data reveal
that the major structural features of genistein pave the way for
synthesis of new genistein derivatives, which may emerge as
novel types of anticancer, estrogenic, and antiosteoporetic
The best known sources of genistein are soy-based foods, such
as soy cheese or soy drinks (i.e., soy milk and soy-based bev-
erages). The content of genistein in mature soybeans has been
shown to range from 5.6 to 276 mg/100 g, and an average
content of 81 mg/100 g is often described for comparative
purposes (59). In addition to genistein, soy foods contain an-
other major isoavone, daidzein, which differs from genistein
by the lack of the hydroxyl group at position 5 (Figure 1).
Both isoflavones may exist in their aglycone or glycoside
forms. The most common glycoside forms of genistein and
daidzein are those of O-b-D-glucoside derivatives at position
7 in both compounds. Because numerous traditional Asian
foods are made from soybeans, the average dietary isoflavone
intake in Asian countries is in the range of 2550 mg/d,
Abbreviations used: ABCG2, ATP-binding cassette subfamily G member 2; AP-1, activator
protein 1; ATO, arsenic trioxide; ATR, ataxia telangiectasia and Rad3-related kinase; Bax,
Bcl-2–associated X protein; Bcl-2, B cell lymphoma 2; BRCA, breast cancer growth
suppressor protein; Cdc2/Cdk1, cell division cycle protein 2 homolog/cyclin-dependent kinase 1;
Cdc25B, cell division cycle 25B; CENPF, centromere protein F; COX-2, cyclooxygenase 2;
CYP, cytochrome P450; dFMGEN, 7-difluoromethyl-5,49-dimethoxygenistein; DKK1,
Dickkopf-related protein 1; EGFR, epidermal growth factor receptor; ER, estrogen receptor;
ERK, extracellular signal-regulated kinase; FoxM1, Forkhead box protein M1; GCSC, gastric
cancer stem cell; Gli1, glioma-associated oncogene family zinc finger 1; GST, glutathione
S-transferase; HCC, hepatocellular carcinoma cell; IFS, isoflavone synthase; INT-1,
integration 1; IkB, inhibitor of NF-kB; KIF, kinesin-like protein; MMP-9, matrix
metalloproteinase 9; PCNA, proliferating cell nuclear antigen; PI3K/Akt, phosphoinositide 3
kinase/Akt; PTEN, phosphatase and tensin homolog; SCLC, small cell lung cancer; THIF,
5,7,39,49tetrahydroxyisoflavone; TNFR-1, tumor necrosis factor receptor 1; TRAIL, tumor
necrosis factor–related apoptosis-inducing ligand; TSA, trichostatin A; UGT,
UDP-glucuronosyltransferase; Wnt/b-catenin, Wingless and integration 1 b-catenin.
Anticancer effects of genistein 409
Downloaded from by guest on 02 December 2020
whereas in Western countries the estimated intake is as low as
Legumes are considered the second most important
source of genistein, at 0.2 to 0.6 mg/100 g, which is present
together with the other related isoavone, daidzein (62).
The genus Lupinus (commonly known as lupin) represents
a typical example of the legume that is now widely cultivated
for its seeds, which possess a nutritional value similar to soy-
bean. Other important legumes are broad beans and chick
peas, which are known to contain significant amounts of
genistein, although less than soybeans. The content of gen-
istein in fruit, nuts, and vegetables can vary considerably; the
estimated range is from 0.03 to 0.2 mg/100 g (63). However,
in some native cherry cultivars of Hungarian origin, genis-
tein concentrations up to 4.4 mg/100 g have been recorded.
An extended list of foods with their genistein content is
available online in several databases (59).
The biotechnological approach used to maximize the iso-
avonoid yield by sprouting seeds is the commonest method
used to improve the nutritional and medicinal values of cer-
tain foods. The metabolic processes of seed germination,
which are characterized by degradation of food reserves
and anabolic processes devoted to the developing embryo,
have been shown to enhance nutritional value primarily
by increasing the content of vitamins and plant secondary
metabolites, such as isoavonoids (59, 6468). Accordingly,
the increased content of genistein and other isoflavonoid
aglycones has been well documented in germinated soybean
seeds and related products (69). During the process of fer-
mentation of soybean products, the content of genistein
and related aglycones increases (70). Through genetic ma-
nipulation, it is also possible to obtain genistein from non-
legume plant sources, such as rice. Cloning the enzyme IFS
from a genistein-rich soybean cultivar resulted in transgenic
rice lines with 30-fold more genistein content (71). With the
medicinal value of genistein and related isoflavonoids now
well recognized, soy-based meat substitutes, soy milk, soy
cheese, and soy yogurt have recently gained popularity in
Europe and the United States.
Various experimental models, including in vivo studies, have
shown that genistein from soy extracts, its free form, and its
glycoside genistin are readily bioavailable. For example, in
freely moving unanesthetized rats with a cannula in the por-
tal vein, genistein was readily bioavailable and was detected
in portal vein plasma 15 min after administration with AUC
values (024 h) of 54 and 24 mmol $h/L for genistein and
genistin, respectively (72). Several studies, however, indi-
cated that the oral bioavailability of genistin is higher than
that of genistein (73). The limitation of genistein bioavaila-
bility after oral administration is generally due to its poor
water solubility (74). Genistein also has a bitter taste (75),
and formulations to overcome both the limitation of bioa-
vailability and acceptable taste are necessary. Extensive me-
tabolism of genistein in the intestine and postabsorption
has been documented both in humans and experimental an-
imals. Among the several metabolites identified in the
blood and excreta are dihydrogenistein, dihydrodaidzein,
69-hydroxy-O-desmethylangolensin, 4-ethylphenol, glucur-
onoide and sulfate conjugates of genistein and its metabolites,
and 4-hydroxyphenyl-2-propionic aid. The gut microflora is
known to cleave the C-ring of the isoflavonoid skeleton to
give 4-hydroxyphenyl-2-propionic acid and dihydrogenis-
tein (7678). The metabolism in the gut wall and liver is
also known to yield glucuronide and sulfated products
(79). Generally, the 3 hydroxyl groups (5, 7, and 49)are
available for conjugation, but genistein-7-glucuronide-49-
sulfate and genistein-49,7-diglucuronide byproduct appears
to be the major metabolite in plasma (80). Some reports
also suggest that conjugation plays a role in rapid elimina-
tion by biliary and urinary excretion (81).
There is no clear evidence that the consumption of large
amounts of isoavones in the diet is harmful in humans, al-
though the multiple and complex effects of these compounds
suggest that the administration of high doses of isoavones
could induce potentially adverse effects (82). However, mini-
mal clinical toxicity in healthy postmenopausal women was
observed after a single dose that exceeded normal dietary
intakes of puried unconjugated isoavones (83). The geno-
toxicity of anticancer agents, such as genistein, may be bene-
cial because they promote cancer cell death by inducing
apoptosis and othercytotoxic processes. However, these agents
FIGURE 2 Chemical structure of glycitein, formononetin, and
biochanin A.
FIGURE 1 Chemical structure of genistein and related
410 Spagnuolo et al.
Downloaded from by guest on 02 December 2020
would also negatively affect normal cells. Genotoxic and po-
tentially adverse effects of genistein (apoptosis, cell growth in-
hibition, topoisomerase inhibition, DNA damage) were
reported in vitro as well as in experimental animals (8487).
However, genistein concentrations used in these studies were
much higher than the physiologically relevant doses achievable
by dietary or pharmacologic intake of soy foods or supple-
ments. In contrast, in vivo studies generally showed negative
genotoxicity results (88). In a study conducted in postmeno-
pausal women aged 4668 y, the administration of a purified
unconjugated isoflavone mixture (genistein, daidzein, and
glycitein) showed minimal toxicity at doses as high as 16 mg
genistein/kg body weight (83).
The potential effects of genistein on fertility and fetus
development have been largely investigated. Some studies
showed that therapeutically relevant doses of genistein
have signicant negative impacts on ovarian differentiation,
estrous cyclicity, and fertility in the rodent model (89).
However, data from human trials are lacking, and hence
studies on the effect of genistein on the human reproductive
function and/or fetal development need to be considered in
the future. Studies in animal models showed that the expo-
sure to genistein during uterine development caused several
adverse effects (89, 90). The conicting results are probably
attributable to differences in the timing of exposure, doses,
and experimental endpoints. It is worth noting that human
fetuses can be exposed to isoavones during the develop-
mental period in the uterus and during infancy via breast
milk (91). Serum genistein concentrations in soy formula
fed infants are from 10- to >100-fold those of the general
population (92). These concentrations can increase blood
genistein concentrations to values compatible with substan-
tial biological estrogenic effects in children. Further epide-
miologic studies are required to determine the beneficial
(and detrimental) effects of genistein exposure, as well as es-
tablishing its safe therapeutic doses.
Genistein and Cancer
Several epidemiologic studies showed a relation between a
soy-rich diet and cancer prevention. These studies arose
from observations that in Asian countries, such as Japan
and China, where diets are high in soy products, the inci-
dence of breast and prostate cancers is lower than that in
the United States and Europe. In fact, several meta-analyses
suggest that the consumption of soy foods is associated
with a reduction in prostate cancer risk in men (9395)
and is inversely associated with breast cancer risk among
Asian women. This association was not confirmed in West-
ern women (9698). Moreover, a recent meta-analysis
found that soy isoflavone intake can lower the risk of breast
cancer in both pre- and postmenopausal women in Asian
countries (99). Furthermore, migration studies showed
an increase in prostate and breast cancer incidence in
Asians after emigration to the United States (100), suggest-
ing that environmental factors and changes in lifestyle, par-
ticularly in dietary practices, affect the etiology of these
types of cancers.
These epidemiologic studies provide the rationale to inves-
tigate at a molecular level how the predominant isoavone
present in soy (i.e., genistein) is able to prevent cancer with
the use of appropriate cellular and animal models. Because
of its pleiotropic activity, genistein shows promising results
as an anticancer agent in preclinical studies, opening the pos-
sibility to verify its clinical efcacy in clinical trials.
During the biogenesis process, genistein is present essen-
tially in its glycosylated form, mostly with a glucose mole-
cule. Although genistein is ingested as genestein glycoside,
after ingestion a deglycosylation process occurs in the small
intestine and the free genistein aglycone is absorbed by the
body, resulting in different pharmacologic effects including
anticancer effects (101). Apart from genistein, the synthetic
derivatives, such as genistein glycosides, are also reported to
possess anticancer activity when assessed in vitro. The anti-
cancer potency of genistein glycosides varies depending on
the sugar groups attached. For example, the addition of acet-
ylated sugar hydroxyls to genistein resulted in more selectiv-
ity toward tumor cells (102). It is worthwhile to note that the
anticancer potency of genistein and its derivatives differs in
different types of cancer, depending on their selectivity to-
ward the target molecules (Figure 3).
Liver cancer
Epidemiologic data. A recent nested case-control study of a
population-based prospective cohort in Japan, which investi-
gated the preventive role of estrogens in primary liver cancer
development, veried whether isoavones were associated
with the risk of liver cancer (103). The authors selected pa-
tients with either hepatitis B or C virus infection at baseline
and measured plasma concentrations of isoavones (genis-
tein, daidzein, glycitein, and equol). The study indicated no
FIGURE 3 Molecular mechanisms mediating the anticancer
effect of genistein: downregulation/suppression, inhibition,
enhancement. AP-1, activator protein 1; Bax, Bcl-2associated X
protein; Bcl-2, B cell lymphoma 2; EGFR, epidermal growth factor
receptor; IkB, inhibitor of NF-kB; KIF20A, kinesin-like protein 20A;
PI3K/Akt, phosphoinositide 3 kinase/Akt; TRAIL, tumor necrosis
factorrelated apoptosis-inducing ligand; TRAIL R, TRAIL death
receptors; Wnt/b-catenin, Wingless and integration 1 b-catenin.
Anticancer effects of genistein 411
Downloaded from by guest on 02 December 2020
association between isoavones and the occurrence of pri-
mary liver cancer risk in middle-aged Japanese women and
men with hepatitis virus infection.
In vitro studies. In vitro studies support the efcacy of gen-
istein as a chemopreventive and/or chemotherapeutic agent
against liver cancer. It induces apoptosis in the following
hepatocellular carcinoma cells (HCCs): Bel 7402 (104),
HuH-7 (105), Hep3B (106), and HepG2 (107). Genistein
may affect HCC progression as a result of its activity on apo-
ptosis and cell cycle regulation (104, 108), acting as a promising
inhibitor of the metastatic process in HCCs. In fact, genistein
has been shown to inhibit the migration of 3 cell lines
(HepG2, SMMC-7721, and Bel-7402 cells) (109). Moreover,
it promotes anti-invasive and antimetastatic effects against
12-O-tetradecanoylphorbol-13-acetate-mediated metastasis
via downregulation of matrix metalloproteinase 9 (MMP-9)
and epidermal growth factor receptor (EGFR) and subsequent
suppression of NF-kB and activator protein 1 (AP-1) transcrip-
tion factors through inhibition of MAPK, inhibitor of NF-kB
(IkB), and phosphoinositide 3 kinase/Akt (PI3K/Akt) signaling
pathways (110).
Several studies also reported the synergistic effect of genis-
tein when administered together with other anticancer drugs.
For example, TNF-related apoptosis-inducing ligand
(TRAIL) is a member of the TNF superfamily, and it has
been shown that many human cancer cell lines are refractory
to TRAIL-induced cell death. The treatment with nontoxic
concentrations of genistein, sufcient to inhibit MAPK acti-
vation, sensitizes human hepatocellular carcinoma Hep3B
cells to TRAIL-mediated apoptosis (111, 112). Genistein
also potentiates the cytotoxic effect of arsenic trioxide
(ATO) against human hepatocellular carcinoma. ATO pos-
sesses limited therapeutic benet in the treatment of solid tu-
mors; genistein, by inhibiting Akt and NF-kB, potentiates the
proliferation-inhibiting and apoptosis-inducing effect of ATO
on human HCC cell lines in vitro (1520 mMgenistein)and
dramatically increases its suppressive effect on both tumor
growth and angiogenesis in nude mice (50 mg genistein/kg
body weight) (113).
In vivo studies. Tumor growth in male BALB/C nu/nu mice
injected with Bel 7402 cells was significantly retarded when
treated with 50 mg genistein/kg body weight in comparison
with control mice; genistein also significantly inhibited the
invasion of Bel 7402 cells into the renal parenchyma of nude
mice with a xenograft transplant by altering cell cycle, apo-
ptosis, and angiogenesis (104). In a different animal model
of liver cancer, HCC-bearing rats (male Wistar rats induced
with N-nitrosoiethylmine by single intraperitoneal injec-
tion and promoted with phenobarbital), it was reported
that genistein efficiently inhibited cell proliferation and in-
duced apoptosis. In fact, the administration of a 15-mg gen-
istein/kg body weight suspension in olive oil stimulate d
caspase-3 activity and remarkably decreased proliferat-
ing cell nuclear antigen (PCNA) in these HCC-bearing rats
Gastric cancer
Epidemiologic data. The benecial role of soybean pro-
ducts against gastric cancer remains debatable from an inter-
ventional point of view. A nested case-control study within
the Korean Multicenter Cancer Cohort suggested that high
serum concentrations of isoavones were associated with a
decreased risk of gastric cancer (115); on the contrary, a par-
allel nested case-control study within the Japan Public
Health CenterBased Prospective Study indicated a null as-
sociation between isoflavone intake and gastric cancer risk
among Japanese men and women (116).
In vitro studies. In preclinical models, genistein was able to
induce apoptosis in primary gastric cancer cells (20 mMfor
2472 h) by downregulating the expression of the antiapop-
totic protein B cell lymphoma 2 (Bcl-2) and upregulating
the expression of proapoptotic Bcl-2associated X protein
(Bax) (117). A similar modification of the Bcl-2:Bax ratio
was considered responsible for the ability of genistein (0.5,
1, and 1.5 mg/kg) to induce apoptosis in SG7901 cells trans-
planted into subcutaneous tissue of nude mice (118). In the
human gastric cancer cell line BGC-823, genistein treatment
inhibited cell proliferation and induced apoptosis in a dose-
and time-dependent manner. In this model, the molecule
exerted a significant inhibitory effect on activation of the
transcription factor NF-kB, causing a reduction in cycloox-
ygenase 2 (COX-2) protein concentrations (119).
The ability of genistein to induce G2/M cell cycle arrest
was tested in SGC-7901 and BGC-823 cells. Here, genistein
(2080 mM) inhibited Akt activation by upregulation of
phosphatase and tensin homolog (PTEN). This event re-
sulted in the decreased phosphorylation of Wee1 on Ser642
and increased phospho-activation of cell division cycle protein
2 homolog/cyclin-dependent kinase 1 (Cdc2/Cdk1) on Thr15,
leading to G2/M arrest (120).
A stable isotope labeling by/with amino acids in cell cul-
ture quantitative proteomics approach was used to identify
the genistein-regulated factors and to investigate the anti-
cancer mechanisms of the molecule. In SGC-7901 cells
treated with 40 mM genistein for 48 h, the expression of 86
proteins involved in the regulation of G2/M transition, cel-
lular growth, and proliferation resulted modulated by genis-
tein, with 49 being upregulated and 37 being downregulated.
In particular, 4 kinesins [kinesin-like protein (KIF) 11,
KIF20A, KIF22, and KIF23] and a KIF, centromere protein
F (CENPF), were found to be significantly downregulated
by genistein, with KIF20A playing an important role in
genistein-induced mitotic arrest (121).
Increasing evidence suggests that gastric cancer stem cells
(GCSCs), a subpopulation of tumor cells capable of self-re-
newal and resistant to chemotherapeutic drugs, are responsi-
ble for the relapse of the disease. Gastric cancer cells treated
with a low dose of genistein (15 mM) inhibited the GCSC-
like properties such as self-renewal ability, drug resistance,
and tumorigenicity, which were associated with the inhibition
of ATP-binding cassette subfamily G member 2 (ABCG2) ex-
pression and extracellular signal-regulated kinase (ERK) 1/2
412 Spagnuolo et al.
Downloaded from by guest on 02 December 2020
activity (122). In GCSCs, genistein can also inhibit glioma-
associated oncogene family zinc finger 1 (Gli1), an activator of
Hedgehog signaling, involved not only in oncogenesis but
also in cancer stemness and overexpression of CD44, a typ-
ical GCSC surface marker. In more detail, it was shown that
the levels of Gli1 and CD44 expression are downregulated
by genistein in GCSCs sorted from MKN45, a human gas-
tric cancer cell line, according to CD44 expression. In
addition, the high cell migration capacity of CD44
was blocked by genistein, suggesting that it can be an effec-
tive agent for gastric cancer therapy by targeting cancer
stem cell-like features (123).
In vivo studies. Tatsuta et al. (124) used, as an in vivo model
of gastric cancer, Wistar rats induced with N-methyl-N-ni-
tro-N-nitroso guanidine and treated with sodium chloride
to enhance induction of gastric carcinogenesis. They showed
that, after 25 wk of the carcinogen treatment, daily injections
of genistein (30 mg/kg body weight) decreased the labeling
index and vessel counts of the antral mucosa and signi-
cantly reduced the incidence of gastric cancers, inducing in-
creased apoptosis and decreased angiogenesis of antral
mucosa and gastric cancers.
Moreover, to investigate the development of cancer ca-
chexia and malignant progression of human stomach cancer,
MKN45cl85 and highly metastatic 85As2mLuc (2 cachexia-
inducing sublines) cells were isolated from the human
stomach cancer cell line MKN-45. These 2 cell lines
induce cachexia at high frequency in mice. It has been
shown that a long duration of treatment with isoavones in-
duced tumor cytostasis, attenuated cachexia, and prolonged sur-
vival in rats (the antitumor effect was graded as AglyMax >
daidzein > genistein) (125).
Lung cancer
Epidemiologic data. Estrogens have been shown to have
mitogenic effects in lung cells and interact with growth factor
pathways in tumorigenesis; epidemiologic studies have pro-
duced conicting results regarding the association between
lung cancer risk and isoavone intake (126128). However,
prospective studies carried out in Asia indicated an inverse as-
sociation in never smokers (129). A nested case-control study
within a large-scale, population-based prospective study in Jap-
anese women with different isoflavone intakes and a high prev-
alence of never smokers revealed an inverse association between
plasma isoflavone concentration and lung cancer risk (130).
In vitro studies. Several in vitro and in vivo studies showed
a protective effect of genistein on lung carcinogenesis when
this compound was either used alone or in association with
other compounds (131134). Genistein showed anticancer
effects on the small cell lung cancer (SCLC) cell line H446;
the molecule induced cell cycle arrest and apoptosis, dereg-
ulating Forkhead box protein M1 (FoxM1) and its target
genes [e.g., cell division cycle 25B (Cdc25B), cyclin B1,
and survivin] (135). Several articles have also shown a syn-
ergistic effect; for example, in A549 lung cancer cells
genistein (510 mM) enhanced apoptosis induced by tri-
chostatin A (TSA) and increased the expression of the death
receptor TNF receptor 1 (TNFR-1), which mediates extrin-
sic apoptosis pathways (134, 136). Patients with non-SCLC
treated with tyrosine kinase inhibitors developed an ac-
quired resistance to this therapy. In a non-SCLC cell line
carrying the T790M mutation in EGFR, genistein associated
with gefitinib, an EGFR tyrosine kinase inhibitor, showed a
synergistic anticancer effect due to apoptosis induction and
inhibition of the key regulators of growth signaling path-
ways, such as Akt (131). The synergistic effect was also con-
firmed in in vivo experiments.
In vivo studies. Gu et al. (104, 108) investigated, in vitro and
in vivo, the inhibitory effects of genistein on the invasive po-
tential of HCCs (Bel 7402 and MHCC97-H). The authors
rst proved the ability of genistein (10 mg/mL) to significantly
inhibit the growth of HCCs in vitro; subsequently, Bel 7402
or MHCC97-H cells were injected in BALB/C nu/nu mice
before the administration of 50 mg genistein/kg body weight.
The tumor growth in genistein-treated nude mice was signif-
icantly lower than that in control mice. The molecule signif-
icantly inhibited the invasion of Bel 7402 cells into the renal
parenchyma of nude mice with xenograft transplant. More-
over, in the in situ xenograft transplantation of MHCC97-H
cells, the number of pulmonary micrometastatic foci after
genistein treatment were significantly lower than in the con-
trol group.
Because of the low bioavailability of genistein in vivo, there
is a growing interest in its derivative, 7-diuoromethyl-5,49-
dimethoxygenistein (dFMGEN), which possesses a better in
vivo bioavailability. An in vitro study showed the efficacy of
dFMGEN in reducing the viability of lung carcinoma A549
cells through induction of G1 phase arrest (137). Moreover,
dFMGEN suppressed tumor growth in vivo and was well
tolerated, confirming its therapeutic potential in the treat-
ment of human lung cancer (137).
Colorectal cancer
Epidemiologic data. The consumption of soy has been
found to reduce colon cancer risk in human and animal
studies (138, 139). Epidemiologic evidence indicates that
phytoestrogens may protect against the development of co-
lorectal cancer (140, 141).
For example, a case-control study evaluated the associa-
tion between dietary phytoestrogen intake (isoavones, li-
gnans, and total phytoestrogens) and colorectal cancer risk
among healthy subjects and those belonging to the popula-
tion-based Ontario Familial Colorectal Cancer Registry. It
was reported that dietary lignin and isoavone intake was
associated with a signicant reduction in colorectal cancer
risk; moreover, it was observed that, with respect to phytoes-
trogen intake, polymorphic genes encoding enzymes in-
volved in the metabolism of phytoestrogens [CYP, catechol
O-methyl transferase, glutathione S-transferases (GSTs),
and UDP-glucuronosyltransferase (UGT)] were not subject
to modifications (142).
Anticancer effects of genistein 413
Downloaded from by guest on 02 December 2020
In vitro studies. Numerous in vitro studies have shown an-
ticancer properties of genistein against colorectal cancer, and
the mechanisms whereby it exerts anticancer effects have been
widely investigated. Genistein efciently suppresses colon
cancer cell growth by attenuating the activity of the PI3K/
Akt pathway (143, 144), which has a critical role in the regu-
lation of colon cancer progression. In colon cancer cells, gen-
istein also affects the expression of ERs and tumor suppressor
genes (145, 146). In addition, it can block uncontrolled cell
growth in a DLD-1 cell line by inhibiting the Wingless and in-
tegration 1 (Wnt) signaling pathway (147). In particular, gen-
istein enhanced gene expression of the Wnt signaling pathway
antagonist, Dickkopf-related protein 1 (DKK1), through the
induction of histone acetylation at the promoter region in
an SW480 human colon cancer cell line (148).
In vivo studies. An in vivo study that used azoxymetha ne as
a chemical inducer of colon cancer in male Sprague-
Dawley rats showed that rats fed 140 mg genistein/kg body
weight from gestation to 13 wk of age showed a downregu-
lation of Wingless and integration 1 b-catenin (Wnt/b-cat-
enin) signaling and a reduction in total aberrant crypts,
confirming the role of this isoflavone in preventing the de-
velopment of early colon neoplasia (149).
Clinical trials. A phase I/II pilot study of genistein use in the
treatment of metastatic colorectal cancer is currently recruit-
ing participants; because of the promising results of the in
vitro and in vivo studies it is expected to have interesting
Breast cancer
Epidemiologic data. Several case-control studies (150, 151)
showed an inverse relation between soy intake and breast
cancer risk; and a prospective cohort study (152) found
that frequent miso soup and isoavone consumption was as-
sociated with a reduced risk of breast cancer in Japan.
Clearly, the chemopreventive effects of soybeans and soy-
containing foods are related to their isoavone content.
In vitro studies. Genistein induced apoptosis in several
breast cancer cell lines and promoted synergistic inhibitory
effects when combined with anticancer drugs. For example,
genistein was shown to induce apoptosis in the low-invasive
(ER-positive) MCF-7 and in the high-invasive (ER-negative)
MDA-MB-231 breast cancer cell lines (10100 mM) (153,
154). Synergistic proapoptotic effects were also described
when genistein was used in combination with adriamycin
and docetaxel in MDA-MB-231 cells (155) and with tamox-
ifen on BT-474 breast cancer cells (156). The main molecu-
lar targets of the molecule in breast cancer cells appear to be
NF-kB (157) and Akt pathways (158). Moreover, genistein
induces in breast and prostate cancer cells the expression
of breast cancer growth suppressor protein (BRCA) 1 and
BRCA2 tumor suppressor genes and the overexpression of
many genes involved in the BRCA1 and BRCA2 pathways
(159). However, it is important to underline the paradoxical
effect of genistein, which stimulates proliferation and
estrogen-sensitive gene expression of the ER-positive breast
cancer cell lines at concentrations of 110 mM (160). At
these low concentrations, genistein abrogates tamoxifen-
associated mammary tumor prevention, but its effect is null
on ER-negative and tamoxifen-resistant breast cancer cells
In vivo studies. The in vitro observations have been con-
rmed in in vivo studies, suggesting that genistein exposure
early in life may reduce the risk of breast cancer (162). On
the contrary, in a preclinical mouse model that resulted in
17b-estradiol blood concentrations similar to those found
in postmenopausal women, dietary genistein in the presence
of low concentrations of circulating E2 acted in an additive
manner to stimulate estrogen-dependent tumor growth
in vivo (163). Results from this study suggest that the con-
sumption of products containing genistein may not be safe
for postmenopausal women with estrogen-dependent breast
Clinical trials. These controversial results have been con-
rmed in human clinical studies, in which, in some cases, pu-
ried genistein did not exert any adverse estrogenic effects on
breast tissue when consumed at a dose of 54 mg/d (164, 165),
whereas others found proestrogenic effects of dietary soy sup-
plementation on breast tissue (166168). Thus, considering
the agonist activity of genistein against ER-a,itsusein
women with established ER-positive breast cancers must be
carefully considered. In this regard, 2 clinical trials based on
the use of genistein in breast cancer, a phase II study entitled
Gemcitabine Hydrochloride and Genistein in Treating
Women with Stage IV Breast Cancer,and a phase I study en-
titled Genistein in Preventing Breast or Endometrial Cancer
in Healthy Postmenopausal Women,have been completed,
although the results are not yet published (169).
Genistein Metabolites and Cancer
Although genistein is reported to be metabolized mainly
through oxidation, sulfation, glucuronidation, hydroxyla-
tion, or methylation (170), the inuence of genistein metab-
olites on its anticancer property is not understood clearly.
Metabolites such as 5,7,39,49-tetrahydroxyisoflavone
(THIF) and 2 glutathinyl conjugates of THIF were identified
in T47D tumorigenic breast epithelial cells that were treated
with genistein. Because THIF has been shown to inhibit
angiogenesis and endothelial cell proliferation (171), it is
worthwhile to note that the formation of THIF during gen-
istein treatment may play a major role in cell cycle arrest, in-
hibition of cellular proliferation, and activation of signaling
pathways such as p38 MAPK, which was observed in T47D
cells. Furthermore, oxidation of THIF to o-quinone along
with formation of hydrogen peroxides and reactive oxygen
species induces DNA strand breakage. This leads to the ac-
tivation of the ataxia telangiectasia and Rad3-related kinase
(ATR) signaling pathway, which activates the kinases in-
volved in DNA damage check-point control (172).
414 Spagnuolo et al.
Downloaded from by guest on 02 December 2020
Conclusions and Recommendations
We reviewed the available evidence on the promising role of
genistein against cancer. Several experimental and clinical in-
vestigations suggest a therapeutic role of genistein on different
types of cancer. The emergence of negative phenomena in can-
cer treatment is well known, such as drug resistance, high risk
of relapse, and the unavailability or poor outcome of therapies,
such as surgery, chemotherapy, phototherapy, and radiother-
apy. Therefore, attention has been paid in recent years to nat-
ural remedies possessing the capacity to improve the efcacy of
chemotherapeutic treatment and to lower adverse effects. Gen-
istein can be included among these compounds because the
molecule shows synergistic behavior when associated with
well-known anticancer drugs, such as adriamycin, docetaxel,
and tamoxifen, suggesting a potential role in combination ther-
apy. However, genistein, as well as other bioactive phytochem-
icals, benets and, at the same time, suffers from 2 apparently
opposite features: high pleiotropy and low bioavailability. The
former refers to the ability of a given compound to act at sev-
eral levels in the cells, triggering at the same time several bio-
chemical pathways involved in the occurrence and
development of cancer (i.e., cell cycle arrest, apoptosis, cell
death). The net result is a synergistic effect that may enhance
the efcacy of a specic drug, even if present in the cells at rel-
atively low concentrations. In this regard, in the previous par-
agraphs, we reviewed several molecular targets of genistein,
such as ER, tyrosine kinases, and pro- and antiapoptotic fac-
tors. Bioavailability was also discussed above, which brings
us to the concept that what we adsorbfrom food is even
more important than what we eat: the plasma concentration
of genistein present in the diet (similar to other bioactive com-
pounds) is significantly lower than the concentrations needed
in experimental models (cell lines and animal studies) to trig-
ger an anticancer response. Therefore, it is reasonable to pre-
dict a significant clinical outcome of genistein when applied
at pharmacologic doses (hundreds of micromolars) and weak
or null effects when the same molecule is administered at che-
mopreventive doses (<1 mM). The reality is probably more
complex than we can expect. In fact, when genistein is ad-
sorbed at low concentrations together with other bioactive
compounds present in the diet, we can postulate pleiotropic
anticancer effects that result from synergistic mechanisms at-
tributable to the plethora of individual compounds (or their
metabolites) deriving from the diet. Alternatively, we can also
hypothesize that genistein possesses, at low doses, effects differ-
ent than those measured at high doses, depending on the cel-
lular background and the molecular target investigated. In this
respect, the ability of genistein to inhibit cell growth in both
hormone-dependent and -independent cancer cells is dose de-
pendent (173). In fact, when genistein concentration increases
from a low nanomolar concentration to hundreds of nanomo-
lars, preferential activation of ER-bis lost and genistein acti-
vates both ERs (aand b); therefore, at least in different
breast cancers, the ratios of the ER subtypes and the concentra-
tions of genistein strongly influence the final effect on hor-
mone-regulated gene expression and cell fate (174).
Future studies are necessary to clarify the potential ther-
apeutic and chemopreventive use of genistein. In particular,
it will be important to investigate the following:
·The pharmacodynamics and pharmacokinetics of genistein
and related compounds in experimental and clinical studies
·Possible strategies to increase the bioavailability of genistein
·The ideal therapeutic dose for treatment of specific types of cancer
·Other molecular mechanisms explaining the anticancer effects
of genistein (e.g., microRNAs)
·Possible interactions between genistein and well-known anti
cancer drugs, by both experimental and clinical studies
Despite the promising results reported in literature, there is
still a long way to go.
All authors read and approved the nal manuscript.
1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C,
Rebelo M, Parkin D, Forman D, Bray F. GLOBOCAN 2012 version 1. 0:
cancer incidence and mortality worldwide. IARC CancerBase Vol. 11.
Lyon (France): International Agency for Research on Cancer; 2013.
[cited 2014 Nov 13]. Available from:
2. Bray F, Ren JS, Masuyer E, Ferlay J. Global estimates of cancer prevalence
for 27 sites in the adult population in 2008. Int J Cancer 2013;132:113345.
3. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global can-
cer statistics. CA Cancer J Clin 2011;61:6990.
4. World Health Organization. The World Health Organizations fight
against cancer: strategies that prevent, cure and care. Geneva (Switzer-
land): WHO Press; 2007.
5. Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE,
Hilpert KF, Griel AE, Etherton TD. Bioactive compounds in foods:
their role in the prevention of cardiovascular disease and cancer.
Am J Med 2002;113:71S88S.
Johnston B, Kas K, La Vecchia C, Mainguet P, et al. Cancer prevention
in Europe: the Mediterranean diet as a protective choice. Eur J Cancer
Prev 2013;22:905.
7. Sung B, Prasad S, Yadav VR, Lavasanifar A, Aggarwal BB. Cancer and
diet: how are they related? Free Radic Res 2011;45:86479.
8. Martínez ME, Marshall JR, Giovannucci E. Diet and cancer preven-
tion: the roles of observation and experimentation. Nat Rev Cancer
9. Le Marchand L, Kolonel LN, Wilkens LR, Myers BC, Hirohata T. An-
imal fat consumption and prostate cancer: a prospective study in Ha-
waii. Epidemiology 1994;5:27682.
10. Giacosa A, Franceschi S, La Vecchia C, Favero A, Andreatta R. Energy
intake, overweight, physical exercise and colorectal cancer risk. Eur J
Cancer Prev 1999;8:S5360.
11. Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moder-
ate alcohol consumption during adult life, drinking patterns, and
breast cancer risk. JAMA 2011;306:188490.
12. Pelucchi C, Tramacere I, Boffetta P, Negri E, Vecchia CL. Alcohol con-
sumption and cancer risk. Nutr Cancer 2011;63:98390.
13. Soobrattee MA, Bahorun T, Aruoma OI. Chemopreventive actions of
polyphenolic compounds in cancer. Biofactors 2006;27:1935.
14. Liu RH. Potential synergy of phytochemicals in cancer prevention:
mechanism of action. J Nutr 2004;134(Suppl):3479S85S.
15. Messina M, Barnes S, Setchell KD. Phyto-oestrogens and breast can-
cer. Lancet 1997;350:9712.
16. Surh Y-J. Cancer chemoprevention with dietary phytochemicals. Nat
Rev Cancer 2003;3:76880.
17. Rajendran P, Ho E, Williams DE, Dashwood RH. Dietary phytochem-
icals, HDAC inhibition, and DNA damage/repair defects in cancer
cells. Clin Epigenetics 2011;3:4.
Anticancer effects of genistein 415
Downloaded from by guest on 02 December 2020
18 . Nabavi SF, Nabavi SM, Setzer W, Nabavi SA, Nabavi SA, Ebrahimzadeh MA.
Antioxidant and antihemolytic activity of lipid-soluble bioactive sub-
stances in avocado fruits. Fruits 2013;68:18593.
19. Nabavi SF, Nabavi SM, Habtemariam S, Moghaddam AH, Sureda A,
Jafari M, Latifi AM. Hepatoprotective effect of gallic acid isolated
from Peltiphyllum peltatum against sodium fluoride-induced oxida-
tive stress. Ind Crops Prod 2013;44:505.
20. Stoner GD, Mukhtar H. Polyphenols as cancer chemopreventive
agents. J Cell Biochem Suppl 1995;22:16980.
21. Amtmann E, Zöller M, Wesch H, Schilling G. Antitumoral activity of
a sulphur-containing platinum complex with an acidic pH optimum.
Cancer Chemother Pharmacol 2001;47:4616.
22. Gould MN. Cancer chemoprevention and therapy by monoterpenes.
Environ Health Perspect 1997;105:9779.
23. Fang MZ, Wang Y, Ai N, Hou Z, Sun Y, Lu H, Welsh W, Yang CS. Tea
polyphenol (2)-epigallocatechin-3-gallate inhibits DNA methyltrans-
ferase and reactivates methylation-silenced genes in cancer cell lines.
Cancer Res 2003;63:756370.
24. Piyanuch R, Sukhthankar M, Wandee G, Baek SJ. Berberine, a natural
isoquinoline alkaloid, induces NAG-1 and ATF3 expression in human
colorectal cancer cells. Cancer Lett 2007;258:23040.
25. Howes MJR, Simmonds MS. The role of phytochemicals as micronutrients
in health and disease. Curr Opin Clin Nutr Metab Care 2014;17:55866.
26. Nabavi SM, Nabavi SF, Eslami S, Moghaddam AH. In vivo protective
effects of quercetin against sodium fluoride-induced oxidative stress in
the hepatic tissue. Food Chem 2012;132:9315.
27. Arts IC, Hollman PC. Polyphenols and disease risk in epidemiologic
studies. Am J Clin Nutr 2005;81(Suppl):317S25S.
28. Khan N, Mukhtar H. Multitargeted therapy of cancer by green tea
polyphenols. Cancer Lett 2008;269:26980.
29. Daglia M. Polyphenols as antimicrobial agents. Curr Opin Biotechnol
30. Daglia M, Di Lorenzo A, Nabavi SF, Talas ZS, Nabavi SM. Polyphe-
nols: well beyond the antioxidant capacity: gallic acid and related
compounds as neuroprotective agents: you are what you eat! Curr
Pharm Biotechnol 2014;15:36272.
31. Jacob V, Hagai T, Soliman K. Structure-activity relationships of flavo-
noids. Curr Org Chem 2011;15:264157.
32. Jaganath IB, Crozier A. Dietary flavonoids and phenolic compounds.
In: Fraga CG, editor. Plant phenolics and human health: biochemistry,
nutrition, and pharmacology. Hoboken (NJ): Wiley. 2010. p. 149.
33. Preedy VR. Isoflavones: chemistry, analysis, function and effects.
Royal Society of Chemistry. Cambridge (United Kingdom); 2012.
34. Banerjee S, Li Y, Wang Z, Sarkar FH. Multi-targeted therapy of cancer
by genistein. Cancer Lett 2008;269:22642.
35. Polkowski K, Mazurek AP. Biological properties of genistein: a review
of in vitro and in vivo data. Acta Pol Pharm 2000;57:13555.
36. Klinge CM. Estrogen receptor interaction with co-activators and co-
repressors. Steroids 2000;65:22751.
37. Kurzer MS. Hormonal effects of soy in premenopausal women and
men. J Nutr 2002;132(Suppl):570S3S.
38. Yoon K, Kwack SJ, Kim HS, Lee BM. Estrogenic endocrine-disrupting
chemicals: molecular mechanisms of actions on putative human dis-
eases. J Toxicol Environ Health B Crit Rev 2014;17:12774.
39. Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH, van der Saag
PT, van der Burg B, Gustafsson JA. Interaction of estrogenic chemicals
and phytoestrogens with estrogen receptor b. Endocrinology 1998;
40. Chang YC, Nair MG, Santell RC, Helferich WG. Microwave-mediated
synthesis of anticarcinogenic isoflavones from soybeans. J Agric Food
Chem 1994;42:186971.
41. Kochs G, Grisebach H. Enzymic synthesis of isoflavones. Eur J Bio-
chem 1986;155:3118.
42. Katsuyama Y, Miyahisa I, Funa N, Horinouchi S. One-pot synthesis of
genistein from tyrosine by coincubation of genetically engineered
Escherichia coli and Saccharomyces cerevisiae cells. Appl Microbiol
Biotechnol 2007;73:11439.
43. Yu O, Jung W, Shi J, Croes RA, Fader GM, McGonigle B, Odell JT.
Production of the isoflavones genistein and daidzein in non-legume
dicot and monocot tissues. Plant Physiol 2000;124:78194.
44. Meng Q-H, Wähälä K, Adlercreutz H, Tikkanen MJ. Antiproliferative
efficacy of lipophilic soy isoflavone phytoestrogens delivered by low
density lipoprotein particles into cultured U937 cells. Life Sci 1999;
45. Somjen D, Amir-Zaltsman Y, Gayer B, Kulik T, Knoll E, Stern N, Lu
LJ, Toldo L, Kohen F. 6-Carboxymethyl genistein: a novel selective
oestrogen receptor modulator (SERM) with unique, differential effects
on the vasculature, bone and uterus. J Endocrinol 2002;173:41527.
46. Matsumoto T, Kobayashi T, Kikuchi T, Honda T, Kamata K. Effects of
dual-action genistein derivatives on relaxation in rat aorta. J Smooth
Muscle Res 2005;41:2333.
47. Zhang LN, Xiao ZP, Ding H, Ge HM, Xu C, Zhu HL, Tan RX. Synthe-
sis and cytotoxic evaluation of novel 7-o-modified genistein deriva-
tives. Chem Biodivers 2007;4:24855.
48. Shimoda K, Kobayashi T, Akagi M, Hamada H, Hamada H. Synthesis
of oligosaccharides of genistein and quercetin as potential anti-
inflammatory agents. Chem Lett 2008;37:8767.
49. Kgomotso T, Chiu F, Ng K. Genistein-and daidzein 7-O-b-D-glucur-
onic acid retain the ability to inhibit copper-mediated lipid oxidation
of low density lipoprotein. Mol Nutr Food Res 2008;52:145766.
50. Fu XH, Wang L, Zhao H, Xiang H-L, Cao JG. Synthesis of genistein
derivatives and determination of their protective effects against vascu-
lar endothelial cell damages caused by hydrogen peroxide. Bioorg Med
Chem Lett 2008;18:5137.
51. Zheng X, Yao X, Liu Y, Zheng Z, Cao J, Liao D. Synthesis and cytotoxic
activity of genistein derivatives. Med Chem Res 2010;19:1296306.
52. Maniewska J, Grynkiewicz G, Szeja W, Hendrich A. Interaction of
genistein benzyl derivatives with lipid bilayers-fluorescence spectro-
scopic and calorimetric study. Bioorg Med Chem 2009;17:25927.
53. ChoiJN,KimD,ChoiHK,YooKM,KimJ,LeeCH.29-Hydroxylation of
genistein enhanced antioxidant and antiproliferative activities in Mcf-7
human breast cancer cells. J Microbiol Biotechnol 2009;19:134854.
54. Zengin G. Synthesis, antimicrobial activity, and structureactivity re-
lationships of eugenol, menthol, and genistein esters. Chem Nat
Compd 2011;47:5505.
55. Fan YE, Li J, Liu R, Ye ZG, Hu JN, Deng ZY, Peng Y. Oral bioavaila-
bility of novel genistein sulfonates and their pre-clinical pharmacoki-
netics. Lat Am J Pharm 2011;30:15829.
56. Hyz K, Kawecki R, Misior A, Bocian W, Bednarek EB, Sitkowski J,
Kozerski L. Genistein binding mode to doubly nicked dumbbell
DNA: dynamic and diffusion ordered NMR study. J Med Chem
57. Li W, Jia HY, He XH, Shi WG, Zhong BH. Novel phenoxyalkylcarbox-
ylic acid derivatives as hypolipidaemic agents. J Enzyme Inhib Med
Chem 2012;27:3118.
58. Qiang X, Sang Z, Yuan W, Li Y, Liu Q, Bai P, Shi Y, Ang W, Tan Z,
Deng Y. Design, synthesis and evaluation of genistein-O-alkylbenzyl-
amines as potential multifunctional agents for the treatment of Alz-
heimers disease. Eur J Med Chem 2014;76:31431.
59. Bhagwat S, Haytowitz DB, Holden JM. USDA database for the isoflavone
content of selected foods. Release 2.0. Bethesda (MD): USDA; 2008.
60. Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and
isoflavone intakes. Nutr Cancer 2006;55:112.
61. van Erp-Baart M-AJ, Brants HA, Kiely M, Mulligan A, Turrini A,
Sermoneta C, Kilkkinen A, Valsta LM. Isoflavone intake in four different
European countries: the VENUS approach. Br J Nutr 2003;89:S2530.
62. Liggins J, Bluck L, Runswick S, Atkinson C, Coward W, Bingham S.
Daidzein and genistein contents of vegetables. Br J Nutr 2000;84:71725.
63. Liggins J, Bluck LJ, Runswick S, Atkinson C, Coward WA, Bingham
SA. Daidzein and genistein content of fruits and nuts. J Nutr Biochem
64. Ahmad S, Pathak D. Nutritional changes in soybean during germina-
tion. J Food Sci Technol 2000;37:6656.
416 Spagnuolo et al.
Downloaded from by guest on 02 December 2020
65. Kim WJ, Lee HY, Won MH, Yoo SH. Germination effect of soybean on
its contents of isoflavones and oligosaccharides. Food Sci Biotechnol
66. Paucar-Menacho LM, Berhow MA, Mandarino JMG, Chang YK, Mejia
EG. Effect of time and temperature on bioactive compounds in germi-
nated Brazilian soybean cultivar BRS 258. Food Res Int 2010;43:185665.
67. Shi H, Nam PK, Ma Y. Comprehensive profiling of isoflavones, phy-
tosterols, tocopherols, minerals, crude protein, lipid, and sugar during
soybean (Glycine max) germination. J Agric Food Chem 2010;58:
68. Yuan JP, Liu YB, Peng J, Wang JH, Liu X. Changes of isoflavone profile
in the hypocotyls and cotyledons of soybeans during dry heating and
germination. J Agric Food Chem 2009;57:900210.
69. Quinhone A Jr., Ida E. Profile of the contents of different forms of
soybean isoflavones and the effect of germination time on these com-
pounds and the physical parameters in soybean sprouts. Food Chem
70. Lee SY, Lee S, Lee S, Oh JY, Jeon EJ, Ryu HS, Lee CH. Primary and
secondary metabolite profiling of doenjang, a fermented soybean paste
during industrial processing. Food Chem 2014;165:15766.
71. Sohn SI, Kim YH, Kim SL, Lee JY, Oh YJ, Chung JH, Lee KR. Genis-
tein production in rice seed via transformation with soybean IFS
genes. Plant Sci 2014;217218:2735.
72. Steensma A, Faassen-Peters MA, Noteborn HP, Rietjens IM. Bioavail-
ability of genistein and its glycoside genistin as measured in the portal
vein of freely moving unanesthetized rats. J Agric Food Chem 2006;
73. Kwon SH, Kang MJ, Huh JS, Ha KW, Lee JR, Lee SK, Lee BS, Han IH,
Lee MS, Lee MW, et al. Comparison of oral bioavailability of genistein
and genistin in rats. Int J Pharm 2007;337:14854.
74. Motlekar N, Khan MA, Youan BBC. Preparation and characterization
of genistein containing poly (ethylene glycol) microparticles. J Appl
Polym Sci 2006;101:20708.
75. Huang AS, Hsieh OAL, Chang SS. Characterization of the nonvolatile
minor constituents responsible for the objectionable taste of defatted
soybean flour. J Food Sci 1982;47:1923.
76. Kobayashi S, Shinohara M, Nagai T, Konishi Y. Transport mechanisms
for soy isoflavones and microbial metabolites dihydrogenistein and di-
hydrodaidzein across monolayers and membranes. Biosci Biotechnol
Biochem 2013;77:22107.
77. Schoefer L, Mohan R, Braune A, Birringer M, Blaut M. Anaerobic C-
ring cleavage of genistein and daidzein by Eubacterium ramulus.
FEMS Microbiol Lett 2002;208:197202.
78. Tamura M, Ohnishi-Kameyama M, Nakagawa H, Tsushida T.
Dihydrogenistein-producing bacterium TM-40 isolated from human
feces. Food Sci Technol Res 2007;13:12932.
79. Shelnutt SR, Cimino CO, Wiggins PA, Ronis MJ, Badger TM. Pharma-
cokinetics of the glucuronide and sulfate conjugates of genistein and
daidzein in men and women after consumption of a soy beverage.
Am J Clin Nutr 2002;76:58894.
80. Hosoda K, Furuta T, Yokokawa A, Ishii K. Identification and quanti-
fication of daidzein-7-glucuronide-49-sulfate, genistein-7-glucuronide-49-
sulfate and genistein-49,7-diglucuronide as major metabolites in human
plasma after administration of kinako. Anal Bioanal Chem 2010;397:
81. Sfakianos J, Coward L, Kirk M, Barnes S. Intestinal uptake and biliary
excretion of the isoflavone genistein in rats. J Nutr 1997;127:12608.
82. Sirtori CR. Risks and benefits of soy phytoestrogens in cardiovascular
diseases, cancer, climacteric symptoms and osteoporosis. Drug Saf
83. Bloedon LT, Jeffcoat AR, Lopaczynski W, Schell MJ, Black TM,
Safety and pharmacokinetics of purified soy isoflavones: single-
dose administration to postmenopausal women. Am J Clin Nutr
84. Klein CB, King AA. Genistein genotoxicity: critical considerations of
in vitro exposure dose. Toxicol Appl Pharmacol 2007;224:111.
85. Touny LHE, Banerjee PP. Identification of both Myt-1 and Wee-1 as
necessary mediators of the p21-independent inactivation of the
Cdc-2/cyclin B1 complex and growth inhibition of TRAMP cancer
cells by genistein. Prostate 2006;66:154255.
86. Snyder RD, Gillies PJ. Reduction of genistein clastogenicity in Chinese
hamster V79 cells by daidzein and other flavonoids. Food Chem Tox-
icol 2003;41:12918.
87. Ramos S. Effects of dietary flavonoids on apoptotic pathways related
to cancer chemoprevention. J Nutr Biochem 2007;18:42742.
88. Michael McClain R, Wolz E, Davidovich A, Bausch J. Genetic toxicity
studies with genistein. Food Chem Toxicol 2006;44:4255.
89. Jefferson WN, Williams CJ. Circulating levels of genistein in the neo-
nate, apart from dose and route, predict future adverse female repro-
ductive outcomes. Reprod Toxicol 2011;31:2729.
90. Rozman KK, Bhatia J, Calafat AM, Chambers C, Culty M, Etzel RA,
Flaws JA, Hansen DK, Hoyer PB, Jeffery EH, et al. NTP-CERHR expert
panel report on the reproductive and developmental toxicity of genis-
tein. Birth Defects Res B Dev Reprod Toxicol 2006;77:485638.
91. Franke AA, Custer LJ, Wang W, Shi CY. HPLC analysis of isoflavo-
noids and other phenolic agents from foods and from human fluids.
Proc Soc Exp Biol Med 1998;217:26373.
92. Cao Y, Calafat AM, Doerge DR, Umbach DM, Bernbaum JC, Twaddle
NC, Ye X, Rogan WJ. Isoflavones in urine, saliva, and blood of infants:
data from a pilot study on the estrogenic activity of soy formula.
J Expo Sci Environ Epidemiol 2009;19:22334.
93. Yan L, Spitznagel EL. Soy consumption and prostate cancer risk in
men: a revisit of a meta-analysis. Am J Clin Nutr 2009;89:115563.
94. Yan L, Spitznagel EL. Meta-analysis of soy food and risk of prostate
cancer in men. Int J Cancer 2005;117:6679.
95. Hwang YW, Kim SY, Jee SH, Kim YN, Nam CM. Soy food consump-
tion and risk of prostate cancer: a meta-analysis of observational stud-
ies. Nutr Cancer 2009;61:598606.
96. Wu AH, Yu MC, Tseng CC, Pike MC. Epidemiology of soy exposures
and breast cancer risk. Br J Cancer 2008;98:914.
97. Zhong X, Zhang C. Soy food intake and breast cancer risk: a meta-
analysis. Wei Sheng Yan Jiu 2012;41:6706.
98. Dong JY, Qin LQ. Soy isoflavones consumption and risk of breast can-
cer incidence or recurrence: a meta-analysis of prospective studies.
Breast Cancer Res Treat 2011;125:31523.
99. Chen M, Rao Y, Zheng Y, Wei S, Li Y, Guo T, Yin P. Association be-
tween soy isoflavone intake and breast cancer risk for pre- and post-
menopausal women: a meta-analysis of epidemiological studies. PLoS
ONE 2014;9:e89288.
100. Shimizu H, Ross RK, Bernstein L, Yatani R, Henderson BE, Mack TM.
Cancers of the prostate and breast among Japanese and white immi-
grants in Los Angeles County. Br J Cancer 1991;63:9636.
101. Polkowski K, Popio1kiewicz J, Krzeczy
nski P, Ramza J, Pucko W,
Zegrocka-Stendel O, Boryski J, Skierski JS, Mazurek AP, Grynkiewicz G,
et al. Cytostatic and cytotoxic activity of synthetic genistein glycosides
against human cancer cell lines. Cancer Lett 2004;203:5969.
102. Popio1kiewicz J, Polkowski K, Skierski JS, Mazurek AP. In vitro toxic-
ity evaluation in the development of new anticancer drugs-genistein
glycosides. Cancer Lett 2005;229:6775.
103. Michikawa T, Inoue M, Sawada N, Tanaka Y, Yamaji T, Iwasaki M,
Shimazu T, Sasazuki S, Mizokami M, Tsugane S. Plasma isoflavones
and risk of primary liver cancer in Japanese women and men with
hepatitis virus infection: a nested case-control study. Cancer Epide-
miol Biomarkers Prev 2015;24:5327.
104. Gu Y, Zhu CF, Iwamoto H, Chen JS. Genistein inhibits invasive poten-
tial of human hepatocellular carcinoma by altering cell cycle, apopto-
sis, and angiogenesis. World J Gastroenterol 2005;11:65127.
105. Mansoor TA, Ramalho RM, Luo X, Ramalhete C, Rodrigues CM,
Ferreira MJ. Isoflavones as apoptosis inducers in human hepatoma
HuH-7 cells. Phytother Res 2011;25:181924.
106. Yeh TC, Chiang PC, Li TK, Hsu JL, Lin CJ, Wang SW, Peng CY, Guh
JH. Genistein induces apoptosis in human hepatocellular carcinomas
via interaction of endoplasmic reticulum stress and mitochondrial in-
sult. Biochem Pharmacol 2007;73:78292.
Anticancer effects of genistein 417
Downloaded from by guest on 02 December 2020
107. Chodon D, Ramamurty N, Sakthisekaran D. Preliminary studies on
induction of apoptosis by genistein on HepG2 cell line. Toxicol In Vi-
tro 2007;21:88791.
108. Gu Y, Zhu CF, Dai YL, Zhong Q, Sun B. Inhibitory effects of genistein
on metastasis of human hepatocellular carcinoma. World J Gastroen-
terol 2009;15:49527.
109. Dai W, Wang F, He L, Lin C, Wu S, Chen P, Zhang Y, Shen M, Wu D,
Wang C. Genistein inhibits hepatocellular carcinoma cell migration by
reversing the epithelial-mesenchymal transition: partial mediation by
the transcription factor NFAT. Mol Carcinog 2015;54:30111.
110. Wang SD, Chen BC, Kao ST, Liu CJ, Yeh CC. Genistein inhibits tumor
invasion by suppressing multiple signal transduction pathways in hu-
man hepatocellular carcinoma cells. BMC Complement Altern Med
111. Jin CY, Park C, Kim GY, Lee SJ, Kim WJ, Choi YH. Genistein enhances
TRAIL-induced apoptosis through inhibition of p38 MAPK signaling
in human hepatocellular carcinoma Hep3B cells. Chem Biol Interact
112. Jin CY, Park C, Moon SK, Kim GY, Kwon TK, Lee SJ, Kim WJ, Choi
YH. Genistein sensitizes human hepatocellular carcinoma cells to
TRAIL-mediated apoptosis by enhancing Bid cleavage. Anticancer
Drugs 2009;20:71322.
113. Ma Y, Wang J, Liu L, Zhu H, Chen X, Pan S, Sun X, Jiang H. Genistein
potentiates the effect of arsenic trioxide against human hepatocellular
carcinoma: role of Akt and nuclear factor-kappa B. Cancer Lett 2011;
114. Chodon D, Banu SM, Padmavathi R, Sakthisekaran D. Inhibition of
cell proliferation and induction of apoptosis by genistein in experi-
mental hepatocellular carcinoma. Mol Cell Biochem 2007;297:
115. Ko KP, Park SK, Park B, Yang JJ, Cho LY, Kang C, Kim CS, Gwack J,
Shin A, Kim Y. Isoflavones from phytoestrogens and gastric cancer
risk: a nested case-control study within the Korean Multicenter Can-
cer Cohort. Cancer Epidemiol Biomarkers Prev 2010;19:1292300.
116. Hara A, Sasazuki S, Inoue M, Miura T, Iwasaki M, Sawada N, Shimazu
T, Yamaji T, Tsugane S. Plasma isoflavone concentrations are not as-
sociated with gastric cancer risk among Japanese men and women.
J Nutr 2013;143:12938.
117. Zhou HB, Chen JJ, Wang WX, Cai JT, Du Q. Apoptosis of human pri-
mary gastric carcinoma cells induced by genistein. World J Gastroen-
terol 2004;10:18225.
118. Zhou HB, Chen JM, Cai JT, Du Q, Wu CN. Anticancer activity of gen-
istein on implanted tumor of human SG7901 cells in nude mice.
World J Gastroenterol 2008;14:62731.
119. Li YS, Wu LP, Li KH, Liu YP, Xiang R, Zhang SB, Zhu LY, Zhang LY.
Involvement of nuclear factor kappa B (NF-kappa B) in the downre-
gulation of cyclooxygenase-2 (COX-2) by genistein in gastric cancer
cells. J Int Med Res 2011;39:214150.
120. Liu YL, Zhang GQ, Yang Y, Zhang CY, Fu RX, Yang YM. Genistein in-
duces G2/M arrest in gastric cancer cells by increasing the tumor sup-
pressor PTEN expression. Nutr Cancer 2013;65:103441.
121. Yan GR, Zou FY, Dang BL, Zhang Y, Yu G, Liu X, He QY. Genistein-
induced mitotic arrest of gastric cancer cells by downregulating
KIF20A: a proteomics study. Proteomics 2012;12:23919.
122. Huang W, Wan C, Luo Q, Huang Z. Genistein-inhibited cancer stem
cell-like properties and reduced chemoresistance of gastric cancer. Int
J Mol Sci 2014;15:343243.
123. Yu D, Shin HS, Lee YS, Lee D, Kim S, Lee YC. Genistein attenuates
cancer stem cell characteristics in gastric cancer through the downre-
gulation of Gli1. Oncol Rep 2014;31:6738.
124. Tatsuta M, Iishi H, Baba M, Yano H, Uehara H, Nakaizumi A. Atten-
uation by genistein of sodium-chloride-enhanced gastric carcinogen-
esis induced by N-methyl-N9-nitro-N-nitrosoguanidine in Wistar rats.
Int J Cancer 1999;80:3969.
125. Yanagihara K, Takigahira M, Mihara K, Kubo T, Morimoto C, Morita Y,
Terawaki K, Uezono Y, Seyama T. Inhibitory effects of isoflavones on
tumor growth and cachexia in newly established cachectic mouse
models carrying human stomach cancers. Nutr Cancer 2013;65:57889.
126. Schabath M B, Hernande z LM, Wu X, Pillow PC, Spi tz MR . Die-
tary phytoestrogens and lung cancer risk. JAMA 2005;294:1493
127. Seow A, Koh WP, Wang R, Lee HP, Yu MC. Reproductive variables,
soy intake, and lung cancer risk among nonsmoking women in the
Singapore Chinese Health Study. Cancer Epidemiol Biomarkers Prev
128. Cutler GJ, Nettleton JA, Ross JA, Harnack LJ, Jacobs DR, Jr., Scrafford
CG, Barraj LM, Mink PJ, Robien K. Dietary flavonoid intake and risk
of cancer in postmenopausal women: the Iowa Womens Health Study.
Int J Cancer 2008;123:66471.
129. Shimazu T, Inoue M, Sasazuki S, Iwasaki M, Sawada N, Yamaji T,
Tsugane S. Isoflavone intake and risk of lung cancer: a prospective
cohort study in Japan. Am J Clin Nutr 2010;91:7228.
130. Shimazu T, Inoue M, Sasazuki S, Iwasaki M, Sawada N, Yamaji T,
Tsugane S. Plasma isoflavones and the risk of lung cancer in women:
a nested case-control study in Japan. Cancer Epidemiol Biomarkers
Prev 2011;20:41927.
131. Zhu H, Cheng H, Ren Y, Liu ZG, Zhang YF, De Luo B. Synergistic in-
hibitory effects by the combination of gefitinib and genistein on
NSCLC with acquired drug-resistance in vitro and in vivo. Mol Biol
Rep 2012;39:49719.
132. Mahmood J, Jelveh S, Calveley V, Zaidi A, Doctrow SR, Hill RP. Mit-
igation of radiation-induced lung injury by genistein and EUK-207.
Int J Radiat Biol 2011;87:889901.
133. Gadgeel SM, Ali S, Philip PA, Wozniak A, Sarkar FH. Genistein en-
hances the effect of epidermal growth factor receptor tyrosine kinase
inhibitors and inhibits nuclear factor kappa B in nonsmall cell lung
cancer cell lines. Cancer 2009;115:216576.
134. Wu TC, Yang YC, Huang PR, Wen YD, Yeh SL. Genistein enhances the
effect of trichostatin A on inhibition of A549 cell growth by increasing
expression of TNF receptor-1. Toxicol Appl Pharmacol 2012;262:24754.
135. Tian T, Li J, Li B, Wang Y, Li M, Ma D, Wang X. Genistein exhibits
anti-cancer effects via down-regulating FoxM1 in H446 small-cell
lung cancer cells. Tumour Biol 2014;35:413745.
136. Shiau RJ, Chen KY, Wen YD, Chuang CH, Yeh SL. Genistein and
b-carotene enhance the growth-inhibitory effect of trichostatin A in
A549 cells. Eur J Nutr 2010;49:1925.
137. Peng B, Cao J, Yi S, Wang C, Zheng G, He Z. Inhibition of prolifera-
tion and induction of G1-phase cell-cycle arrest by dFMGEN, a novel
genistein derivative, in lung carcinoma A549 cells. Drug Chem Toxicol
138. Messina M, Bennink M. Soyfoods, isoflavones and risk of colonic can-
cer: a review of the in vitro and in vivo data. Baillieres Clin Endocrinol
Metab 1998;12:70728.
139. Thiagarajan DG, Bennink MR, Bourquin LD, Kavas FA. Prevention of
precancerous colonic lesions in rats by soy flakes, soy flour, genistein,
and calcium. Am J Clin Nutr 1998;68:1394S9S.
140. Spector D, Anthony M, Alexander D, Arab L. Soy consumption and
colorectal cancer. Nutr Cancer 2003;47:112.
141. Rossi M, Negri E, Talamini R, Bosetti C, Parpinel M, Gnagnarella P,
Franceschi S, Dal Maso L, Montella M, Giacosa A, et al. Flavonoids
and colorectal cancer in Italy. Cancer Epidemiol Biomarkers Prev
142. Cotterchio M, Boucher BA, Manno M, Gallinger S, Okey A, Harper P.
Dietary phytoestrogen intake is associated with reduced colorectal
cancer risk. J Nutr 2006;136:304653.
143. Kim EJ, Shin HK, Park JH. Genistein inhibits insulin- like g rowth
factor-I receptor signaling in HT-29 human colon cancer cells: a pos-
sible mechanism of the growth inhibitory effect of Genistein. J Med
Food 2005;8:4318.
144. Su SJ, Chow NH, Kung ML, Hung TC, Chang KL. Effects of soy iso-
flavones on apoptosis induction and G2-M arrest in human hepatoma
cells involvement of caspase-3 activation, Bcl-2 and Bcl-XL downregu-
lation, and Cdc2 kinase activity. Nutr Cancer 2003;45:11323.
145. Bielecki A, Roberts J, Mehta R, Raju J. Estrogen receptor-beta medi-
ates the inhibition of DLD-1 human colon adenocarcinoma cells by
soy isoflavones. Nutr Cancer 2011;63:13950.
418 Spagnuolo et al.
Downloaded from by guest on 02 December 2020
146. Qi W, Weber CR, Wasland K, Savkovic SD. Genistein inhibits proliferation
of colon cancer cells by attenuating a negative effect of epidermal growth
factor on tumor suppressor FOXO3 activity. BMC Cancer 2011;11:219.
147. Zhang Y, Chen H. Genistein attenuates WNT signaling by up-regulating
sFRP2 in a human colon cancer cell line. Exp Biol Med (Maywood)
148. Wang H, Li Q, Chen H. Genistein affects histone modifications on
Dickkopf-related protein 1 (DKK1) gene in SW480 human colon can-
cer cell line. PLoS ONE 2012;7:e40955.
149. Zhang Y, Li Q, Zhou D, Chen H. Genistein, a soya isoflavone, prevents
azoxymethane-induced up-regulation of WNT/beta-catenin signalling
and reduces colon pre-neoplasia in rats. Br J Nutr 2013;109:3342.
150. Dai Q, Shu XO, Jin F, Potter JD, Kushi LH, Teas J, Gao YT, Zheng W,
et al. Population-based case-control study of soyfood intake and breast
cancer risk in Shanghai. Br J Cancer 2001;85:3728.
151. Wu AH, Yu MC, Tseng CC, Twaddle NC, Doerge DR. Plasma isofla-
vone levels versus self-reported soy isoflavone levels in Asian-American
women in Los Angeles County. Carcinogenesis 2004;25:7781.
152. Yamamoto S, Sobue T, Kobayashi M, Sasaki S, Tsugane S. Soy, isofla-
vones, and breast cancer risk in Japan. J Natl Cancer Inst 2003;95:90613.
153. Liu Y, Zhang YM, Song DF, Cui HB. Effect of apoptosis in human
breast cancer cells and its probable mechanisms by genistein. Wei
Sheng Yan Jiu 2005;34:679.
154. Hsieh CY, Santell RC, Haslam SZ, Helferich WG. Estrogenic effects of
genistein on the growth of estrogen receptor-positive human breast
cancer (MCF-7) cells in vitro and in vivo. Cancer Res 1998;58:38338.
155. Satoh H, Nishikawa K, Suzuki K, Asano R, Virgona N, Ichikawa T,
Hagiwara K, Yano T. Genistein, a soy isoflavone, enhances necrotic-
like cell death in a breast cancer cell treated with a chemotherapeutic
agent. Res Commun Mol Pathol Pharmacol 2003;113114:14958.
156. Mai Z, Blackburn GL, Zhou JR. Genistein sensitizes inhibitory effect of
tamoxifen on the growth of estrogen receptor-positive and HER2-over-
expressing human breast cancer cells. Mol Carcinog 2007;46:53442.
157. Li Y, Ahmed F, Ali S, Philip PA, Kucuk O, Sarkar FH. Inactivation of
nuclear factor kappaB by soy isoflavone genistein contributes to in-
creased apoptosis induced by chemotherapeutic agents in human can-
cer cells. Cancer Res 2005;65:693442.
158. Gong L, Li Y, Nedeljkovic-Kurepa A, Sarkar FH. Inactivation of NF-
kappaB by genistein is mediated via Akt signaling pathway in breast
cancer cells. Oncogene 2003;22:47029.
159. Caëtano B, Le Corre L, Chalabi N, Delort L, Bignon YJ, Bernard-
Gallon DJ. Soya phytonutrients act on a panel of genes implicated
with BRCA1 and BRCA2 oncosuppressors in human breast cell lines.
Br J Nutr 2006;95:40613.
160. Seo HS, DeNardo DG, Jacquot Y, Laios I, Vidal DS, Zambrana CR,
Leclercq G, Brown PH. Stimulatory effect of genistein and apigenin
on the growth of breast cancer cells correlates with their ability to ac-
tivate ER alpha. Breast Cancer Res Treat 2006;99:12134.
161. Liu B, Edgerton S, Yang X, Kim A, Ordonez-Ercan D, Mason T, Alvar-
ez K, McKimmey C, Liu N, Thor A. Low-dose dietary phytoestrogen
abrogates tamoxifen-associated mammary tumor prevention. Cancer
Res 2005;65:87986.
162. Lamartiniere CA, Zhang JX, Cotroneo MS. Genistein studies in rats:
potential for breast cancer prevention and reproductive and develop-
mental toxicity. Am J Clin Nutr 1998;68:1400S5S.
163. Ju YH, Allred KF, Allred CD, Helferich WG. Genistein stimulates
growth of human breast cancer cells in a novel, postmenopausal ani-
mal model, with low plasma estradiol concentrations. Carcinogenesis
164. Marini H, Bitto A, Altavilla D, Burnett BP, Polito F, Di Stefano V,
Minutoli L, Atteritano M, Levy RM, DAnna R, et al. Breast safety and
efficacy of genistein aglycone for postmenopausal bone loss: a follow-
up study. J Clin Endocrinol Metab 2008;93:478796.
165. Atteritano M, Pernice F, Mazzaferro S, Mantuano S, Frisina A, DAnna
R, Cannata ML, Bitto A, Squadrito F, Frisina N, et al. Effects of phy-
toestrogen genistein on cytogenetic biomarkers in postmenopausal
women: 1 year randomized, placebo-controlled study. Eur J Pharma-
col 2008;589:226.
166. McMichael-Phillips DF, Harding C, Morton M, Roberts SA, Howell A,
Potten CS, Bundred NJ. Effects of soy-protein supplementation on ep-
ithelial proliferation in the histologically normal human breast. Am J
Clin Nutr 1998;68(Suppl):1431S5S.
167. Hargreaves DF, Potten CS, Harding C, Shaw LE, Morton MS, Roberts
SA, Howell A, Bundred NJ. Two-week dietary soy supplementation
has an estrogenic effect on normal premenopausal breast. J Clin En-
docrinol Metab 1999;84:401724.
168. Khan SA, Chatterton RT, Michel N, Bryk M, Lee O, Ivancic D, Heinz
R, Zalles CM, Helenowski IB, Jovanovic BD, et al. Soy isoflavone sup-
plementation for breast cancer risk reduction: a randomized phase II
trial. Cancer Prev Res (Phila) 2012;5:30919.
169. [cited 2014 Nov 13]. Available from:
170. Nguyen DT, Hernandez-Montes E, Vauzour D, Schönthal AH, Rice-
Evans C, Cadenas E, Spencer JP. The intracellular genistein metabolite
5,7,39,49-tetrahydroxyisoflavone mediates G2-M cell cycle arrest in
cancer cells via modulation of the p38 signaling pathway. Free Radic
Biol Med 2006;41:122539.
171. Kiriakidis S, gemeier O, Starcke S, Dombrowski F, Hahne JC,
Pepper M, Jha HC, Wernert N. Novel tempeh (fermented soyabean)
isoflavones inhibit in vivo angiogenesis in the chicken chorioallantoic
membrane assay. Br J Nutr 2005;93:31723.
172. Vauzour D, Vafeiadou K, Rice-Evans C, Cadenas E, Spencer JP. Inhi-
bition of cellular proliferation by the genistein metabolite 5,7,39,49-
tetrahydroxyisoflavone is mediated by DNA damage and activation
of the ATR signalling pathway. Arch Biochem Biophys 2007;468:
173. Russo M, Spagnuolo C, Tedesco I, Russo GL. Phytochemicals in
cancer prevention and therapy: truth or dare? Toxins 2010;2:517
51. [cited 2014 Nov 13]. Available from: http://www.clinicaltrials.
174. Ch ang EC, Charn TH, Park SH, Helferich WG, Ko mm B,
Katzenellenbogen JA, Katzenellenbogen BS. Estrogen receptors
alpha and beta as determinants of gene expression: influence
of ligand, dose, and chromatin binding. Mol Endocrinol 2008;
Anticancer effects of genistein 419
Downloaded from by guest on 02 December 2020
... In addition, there is an upregulation of Notch-1 and other signalling pathways (caspases, bcl-2/Bax), including inflammatory mediator (NF-B), p53 leads to apoptosis [54]. Inflammation is triggered by decreased blood flow, activation of intravascular leukocytes, and release of proinflammatory mediators such as interleukin-1 (IL-1) [55]. Tumor necrosis factor (TNF) can cause further tissue damage. ...
Full-text available
Neurodegenerative diseases (NDDs) are generally identified by the sudden decrease in neuronal disruption in normal and subsequent cell death in the brain or peripheral nervous system underlying conditions, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis, lack of effective treatments shown to slow down their progression. Natural compounds derived from plants have demonstrated potential efficacy in combating various diseases, including neurodegenerative disorders. This review article evaluates the molecular targets and therapeutic potential of isoflavones, with a particular focus on genistein, in the treatment of neurodegenerative diseases. Both in vivo and in vitro studies have indicated the neuroprotective effects against NDDs. We aim to provide a comprehensive overview of the role played by genistein in delaying the development, mechanisms of action and progression of neurodegenerative diseases. Additionally, we examine the current evidence supporting the use of genistein in preclinical and clinical studies, highlighting its potential therapeutic benefits in neurodegenerative disorders. However, further research is needed to elucidate optimal dosage, bioavailability, and long-term safety profiles, also to investigate potential synergistic effects with existing therapies. The insights provided in this review may contribute to the development of novel therapeutic strategies for the management of these devastating disorders.
... Genistein (GEN, Fig. 1a), a polyphenolic isoflavone with a rich plant-based source [1], is a significant member of natural products. Based on modern pharmacological studies, GEN is demonstrated to have a wide range of potential health-promoting bioactivities, including anti-oxidant [2], anti-inflammatory [3], anti-cancer [4,5], anti-diabetic [6], hepatoprotective [7] and cardioprotective effects [8,9]. Besides, GEN can lower blood lipids and blood pressure as well as treat osteoporosis and menopausal syndrome in women [10][11][12]. ...
Full-text available
With various potential health-promoting bioactivities, genistein has great prospects in treatment of a series of complex diseases and metabolic syndromes such as cancer, diabetes, cardiovascular diseases, menopausal symptoms and so on. However, poor solubility and unsatisfactory bioavailability seriously limits its clinical application and market development. To optimize the solubility and bioavailability of genistein, the cocrystal of genistein and piperazine was prepared by grinding assisted with solvent based on the concept of cocrystal engineering. Using a series of analytical techniques including single-crystal X-ray diffraction, powder X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis, the cocrystal was characterized and confirmed. Then, structure analysis on the basis of theoretical calculation and a series of evaluation on the stability, dissolution and bioavailability were carried out. The results indicated that the cocrystal of genistein and piperazine improved the solubility and bioavailability of genistein. Compared with the previous studies on the cocrystal of genistein, this is a systematic and comprehensive investigation from the aspects of preparation, characterization, structural analysis, stability, solubility and bioavailability evaluation. As a simple, efficient and green approach, cocrystal engineering can pave a new path to optimize the pharmaceutical properties of natural products for successful drug formulation and delivery. Graphical Abstract
... Moreover, this substance can lower the expression of specific QS-controlled genes (namely rhlI, rhlR, phzA1, rhlA, lasI, lasR, lasA, and lasB) in P. aeruginosa PAO1 [95]. As an isoflavone compound, genistein can be derived from most leguminous plant foods [96]. Aerolysin is an important virulence factor of pathogenic Aeromonas. ...
Full-text available
The overuse of antibiotics and the emergence of multiple-antibiotic-resistant pathogens are becoming a serious threat to health security and the economy. Reducing antimicrobial resistance requires replacing antibiotic consumption with more biocontrol strategies to improve the immunity of animals and humans. Probiotics and medicinal plants have been used as alternative treatments or preventative therapies for a variety of diseases caused by bacterial infections. Therefore, we reviewed some of the anti-virulence and bacterial toxin-inhibiting strategies that are currently being developed; this review covers strategies focused on quenching pathogen quorum sensing (QS) systems, the disruption of biofilm formation and bacterial toxin neutralization. It highlights the probable mechanism of action for probiotics and medicinal plants. Although further research is needed before a definitive statement can be made on the efficacy of any of these interventions, the current literature offers new hope and a new tool in the arsenal in the fight against bacterial virulence factors and bacterial toxins.
Full-text available
Malignant melanoma is a fatal disease with an increasing global incidence. Despite numerous studies focused on anti-cancer drugs, a variety of side effects of cancer treatment remain challenging. Thus, there is a pressing need to identify novel anti-cancer agents with minimal cytotoxicity and side effects. DB3 (1,3,7,9-tetrahydroxy-2,8-dimethyl-4,6-di[ethanoyl]dibenzofuran) is a member of the dibenzofuran family and is extracted from Ramalina terebrata (Antarctic lichen). We investigated if DB3 exerted an antitumor effect on B16F10 melanoma cells. The results revealed that DB3 exerted time- and dose-dependent reduction of cell viability by inducing apoptosis and significantly suppressing cell proliferation through cell cycle arrest in the G0/G1 phase in B16F10 melanoma cells. Additionally, DB3 impeded the migration and invasiveness of B16F10 cells. Subsequently, we observed that DB3 decreased the expression levels of Cdk4/Cyclin D1 and the phosphorylation of p38, JNK, ERK, and AKT. Furthermore, DB3 decreased melanoma tumor growth in a mouse tumor syngraft model. Based on these findings, we propose that DB3 possesses potential for use as an anti-cancer agent for melanoma treatment.
Full-text available
Breast and lung cancer are two of the most lethal forms of cancer, responsible for a disproportionately high number of deaths worldwide. Both doctors and cancer patients express alarm about the rising incidence of the disease globally. Although targeted treatment has achieved enormous advancements, it is not without its drawbacks. Numerous medicines and chemotherapeutic drugs have been authorized by the FDA; nevertheless, they can be quite costly and often fall short of completely curing the condition. Therefore, this investigation has been conducted to identify a potential medication against breast and lung cancer through structural modification of genistein. Genistein is the active compound in Glycyrrhiza glabra (licorice), and it exhibits solid anticancer efficiency against various cancers, including breast cancer, lung cancer, and brain cancer. Hence, the design of its analogs with the interchange of five functional groups—COOH, NH2 and OCH3, Benzene, and NH-CH2-CH2-OH—have been employed to enhance affinities compared to primary genistein. Additionally, advanced computational studies such as PASS prediction, molecular docking, ADMET, and molecular dynamics simulation were conducted. Firstly, the PASS prediction spectrum was analyzed, revealing that the designed genistein analogs exhibit improved antineoplastic activity. In the prediction data, breast and lung cancer were selected as primary targets. Subsequently, other computational investigations were gradually conducted. The mentioned compounds have shown acceptable results for in silico ADME, AMES toxicity, and hepatotoxicity estimations, which are fundamental for their oral medication. It is noteworthy that the initial binding affinity was only −8.7 kcal/mol against the breast cancer targeted protein (PDB ID: 3HB5). However, after the modification of the functional group, when calculating the binding affinities, it becomes apparent that the binding affinities increase gradually, reaching a maximum of −11.0 and −10.0 kcal/mol. Similarly, the initial binding affinity was only −8.0 kcal/mol against lung cancer (PDB ID: 2P85), but after the addition of binding affinity, it reached −9.5 kcal/mol. Finally, a molecular dynamics simulation was conducted to study the molecular models over 100 ns and examine the stability of the docked complexes. The results indicate that the selected complexes remain highly stable throughout the 100-ns molecular dynamics simulation runs, displaying strong correlations with the binding of targeted ligands within the active site of the selected protein. It is important to further investigate and proceed to clinical or wet lab experiments to determine the practical value of the proposed compounds.
A collection of current knowledge of phytochemicals and health. Interest in phenolic phytochemicals has increased as scientific studies indicate these compounds exhibit potential health benefits. With contributions from world leaders in this research area, Plant Phenolics and Human Health: Biochemistry, Nutrition, and Pharmacology offers an essential survey of the current knowledge on the capacity of specific micronutrients present in ordinary diets to fight disease. The coverage in this resource: Explains the presence and biochemical properties of phenolics present in fruits and vegetables, as well as in foods derived from their plant sources. Provides biochemical explanations on how certain plant phenolics fight cardiovascular and neurodegenerative diseases, cancer, and other widespread pathologies. Focuses on certain phenolics, e.g., flavonoids, stilbenes, and curcuminoids, and provides insights on the biochemical bases used to define their significance in the diet as well as their recommended consumption requirements and toxicity. Appropriate for graduate and upper-level undergraduate courses in human and animal nutrition, basic nutritional biology, physiology, pharmacology, and other health-related disciplines, Plant Phenolics and Human Health: Biochemistry, Nutrition, and Pharmacology serves as both an invaluable supplementary classroom text and a self-teaching guide for professionals interested in defining the association between diet and health from classical, alternative, and complementary biomedical perspectives.
Conference Paper
Asian women and men who consume traditional diet high in soy products have low incidences of breast and prostate cancers, respectively. Yet Asians who immigrate to the United States and adopt a Western diet lose this protection. We investigated the potential of genistein, a component of soy, to protect against breast cancer and to cause reproductive and developmental toxicity. Our study showed that injections of genistein in rats during the prepubertal period resulted in a 50% reduction of chemically induced mammary tumorigenesis. Studies in mammary whole mounts revealed that prepubertal genistein exposure resulted in fewer terminal end buds and more lobules type LI. Cell proliferation in the terminal end buds of adult rats treated prepubertally with genistein was less than that in animals treated with the vehicle (dimethyl sulfoxide). Reproductive and developmental toxicity studies did not find significant alterations to fertility, number of male and female offspring, body weight, anogenital distance, vaginal opening, testes descent, estrus cycle, or follicular development. We concluded that pharmacologic doses of genistein given to immature rats enhance mammary gland differentiation, resulting in a significantly less proliferative gland that is not as susceptible to mammary cancer. We speculate that breast cancer protection in Asian women consuming traditional soy-containing diets is, in part, derived from early exposure to genistein-containing soy. We believe that early programming events are essential for cancer protection benefits.
Conference Paper
Epidemiological studies have consistently shown that regular consumption of fruits and vegetables is strongly associated with reduced risk of developing chronic diseases, such as cancer and cardiovascular disease. It is now widely believed that the actions of the antioxidant nutrients alone do not explain the observed health benefits of diets rich in fruits and vegetables, because taken alone, the individual antioxidants studied in clinical trials do not appear to have consistent preventive effects. Work performed by our group and others has shown that fruits and vegetable phytochemical extracts exhibit strong antioxidant and anti proliferative activities and that the major part of total antioxidant activity is from the combination of phytochemicals. We proposed that the additive and synergistic effects of phytochemicals in fruits and vegetables are responsible for these potent antioxidant and anticancer activities and that the benefit of a diet rich in fruits and vegetables is attributed to the complex mixture of phytochemicals present in whole foods. This explains why no single antioxidant can replace the combination of natural phytochemicals in fruits and vegetables to achieve the health benefits. The evidence suggests that antioxidants or bioactive compounds are best acquired through whole-food consumption, not from expensive dietary supplements. We believe that a recommendation that consumers eat 5 to 10 servings of a wide variety of fruits and vegetables daily is an appropriate strategy for significantly reducing the risk of chronic diseases and to meet their nutrient requirements for optimum health.