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Introduction
Despite significant investments in capital, manpower, and
intellectual innovations for the development of cancer
therapies over the past several decades, cancer still remains the
second leading cause of death in the United
States[1]. There-fore, cancer prevention has become an important avenue
through which the fight against cancer could be feasible.
Cancer chemoprevention applies specific natural or synthetic
chemical compounds to inhibit or reverse carcinogenesis
and to suppress the development of cancer from
premalignant lesions. The emerging field of cancer prevention by
chemopreventive agents offers significant promise for
reducing the incidence and mortality of cancer. Several
studies have shown that the incidence of cancer could be
decreased by chemoprevention[2_4]. Chemoprevention
appears to be a promising avenue for reducing cancer
incidence in both high-risk groups and the general population
with a low risk of developing cancer. Because of its
promising effects, chemoprevention has been increasingly
recognized as a powerful tool by cancer investigators and the
National Cancer Institute[5].
Chemopreventive agents may exert their effects either
by blocking or metabolizing carcinogens or by inhibiting
tumor cell growth. Another important benefit of
chemopre-ventive agents is their non-toxic nature. Therefore,
chemo-preventive agents have been recently used in cancer
treatment in combination with conventional chemotherapeutics
or radiotherapy. In vitro and in
vivo preclinical studies have demonstrated that chemopreventive agents could enhance
the antitumor activity of
chemotherapeutics[6_11], improving treatment outcome. The combination treatment may also
decrease the systemic toxicity caused by chemotherapies
because lower doses of therapeutic agents could be used,
and as such, no systemic toxicity has been found from
chemopreventive agents. Growing in vitro and
in vivo data have shown that chemopreventive agents enhance the
efficacy of chemotherapy and radiotherapy in various cancers
through the regulation of Akt, NF-κB, c-Myc, cyclooxygenase
(COX)-2, apoptotic, and other pathways, suggesting a novel
and multitargeted therapeutic strategy against
cancer[6,7,11_14]. This strategy opens a new avenue from cancer prevention
to cancer treatment.
Chemopreventive agents enhance antitumor activity of conventional cancer therapies
Most of the chemopreventive agents currently being
studied are natural products or their derivatives. Many
natural compounds, particularly plant products and
dietary constituents, have been found to exhibit cancer
chemopre-ventive activities both in
vitro and in vivo[15,16]. Drug
development from natural products is a
rapidly emerging and highly promising strategy to identify novel anticancer agents. In
recent years, novel combination treatments with conventional
cancer therapies and chemopreventive agents have received
much attention in cancer research. Experimental studies and
clinical trials have demonstrated the beneficial effects of
chemopreventive agents, including soy isoflavone,
curcu-min, epigallocatechin-3-gallate (EGCG), non-steroidal
anti-inflammatory drugs (NSAIDs), resveratrol, indole-3-carbinol
(I3C), and 3,3'-diindolyl-methane (DIM) in cancer
prevention and treatment.
Evidence from epidemiologic and in vivo studies show
a decreased risk of cancer associated with soy
consumption[17]. Soy isoflavone genistein is believed to be
responsible for the decreased risk of cancer. Isoflavone genistein
has been found to inhibit the growth of various cancer cells
in vitro and in vivo[17]. More importantly, the published
studies have shown that isoflavone genistein could
potentiate the antitumor effects of chemotherapeutic agents in
various cancers in vitro and in vivo in preclinical studies.
We have reported that in vitro genistein potentiated growth
inhibition and apoptotic cell death caused by cisplatin,
docetaxel, doxorubicin, gemcitabine, and CHOP
(cyclophos-phamidine, doxorubicin, vincristine, prednisone) in lymphoma
and cancers of prostate, breast, pancreas, and
lung[6,7,12,18]. We have also found that dietary genistein
in vivo could
enhance the antitumor activities of gemcitabine and docetaxel
in a tumor model, resulting in apoptotic cell death and the
inhibition of tumor growth[6,7]. Similar observations by other
investigators have also showed that the antitumor effects of
chemotherapeutics, including 5-fluorouracil (5-FU),
adriamy-cin, and tamoxifen could be potentiated by
genistein[13,19,20]. Genistein also enhanced the antitumor effect of bleomycin
in HL-60 cells, but not in normal lymphocytes in an
in vitro study[21]. The synergistic action of genistein and cisplatin
or carmustine (BCNU) on the growth inhibition of
glioblastoma and medulloblastoma cells has also been observed[22,23]. These reports suggest that isoflavone genistein is
not just a chemopreventive agent, but could also be used as
a potential therapeutic agent in combination with other
chemotherapeutics for cancer treatment. In radiotherapy,
experimental studies have demonstrated that the
combination of genistein and radiation exerted enhanced inhibitory
effects on DNA synthesis, cell growth, colony formation,
and metastasis[24,25]. Genistein also enhanced
radiosensitivity in human esophageal and cervical cancer
cells[26,27], suggesting the beneficial effects of genistein in cancer
radio-therapy.
To enhance the antitumor activity of isoflavone, several
isoflavone derivatives have been synthesized and used in
in vitro and in vivo experiments and in clinical trials. These
compounds have shown a low IC50 in the inhibition of
cancer cell growth in vitro. Moreover, at low concentrations,
these compounds were able to enhance the antitumor
activity of clinically available chemotherapeutic agents,
suggesting their potent effects as therapeutic agents for
combination treatment. Phenoxodiol is one such analog of
isoflav-one genistein and has shown a broad-spectrum, anticancer
effect. In an animal study, phenoxodiol inhibited
dimethyl-benz(a)anthracene (DMBA)-induced mammary
carcinogenesis in female Sprague-Dawley rats, suggesting that
phenoxodiol is an effective chemopreventive agent against
DMBA-induced oncogenesis[28]. In experimental studies and
clinical trials, phenoxodiol has been used both as a
mono-therapy and in combination with standard
chemothera-peutics. These studies have shown that in some cancers
phenoxodiol appears to be strong enough to work on its
own as a monotherapy. However, one of the major benefits
of phenoxodiol is its ability to sensitize cancer cells to the
antitumor effects of conventional
chemotherapeutics[29]. It has been found in cancer cells that are susceptible to the
effects of standard chemotherapeutics that phenoxodiol
increases their sensitivity to those agents. In cancer cells that
have become resistant to the effects of conventional
chemo-therapeutics, phenoxodiol restores
chemosensitivity[14,30]. By exposing chemoresistant cancer cells to phenoxodiol first,
long-standing drug resistance is removed, making cancer
cells susceptible once again to standard chemotherapeutics,
such as cisplatin, carboplatin, taxanes, and gemcitabine.
Phenoxodiol is currently undergoing clinical studies in the
USA and Australia. So far, phase I/II clinical trials have
shown some disease stabilization without severe
toxicity[31].
In addition to isoflavone and its derivatives, other
chemopreventive agents have shown their effects on the
enhancement of the antitumor activities of
chemotherapeutic agents. Curcumin has been found to inhibit the
carcinogenic activity of azoxymethane or DMBA in the colon or
orally in rats[32,33]. Curcumin also inhibited cancer cell growth
and induced apoptotic cell death in various cancers
[34]. Moreover, curcumin and celecoxib synergistically inhibited
the growth of colorectal cancer
cells[35]. Curcumin also potentiated the antitumor activities of cisplatin, doxorubicin,
and Taxol in HA22T/VGH hepatic cancer cells, HeLa cells, or
CAOV3 and SKOV3 ovarian cancer
cells[8_10]. In addition, the combination treatment with curcumin and TRAIL
increased the number of hypodiploid cells and induced DNA
fragmentation in LNCaP cells[36]. More recently, curcumin
was found to sensitize pancreatic cancer cells to
gemcitabine-induced killing[37]. In cancer radiotherapy, curcumin at a low
concentration also showed significant enhancement to
radiation-induced clonogenic inhibition and apoptosis in
PC-3 prostate cancer cells[38]. These results demonstrated that
curcumin is a potent agent in cancer prevention and therapy.
Epidemiologic evidence showed that consumption of
green tea, which contains EGCG, significantly decreased
overall cancer incidence[39]. As an antioxidant and
photoprotective agent, EGCG promotes cell cycle arrest and
apoptosis in cancer cells through the modulations of
cyclin/CDK and Bcl-2 family
proteins[40]. EGCG in vivo also inhibits
tumor promotion and metastasis in murine
melanoma[41]. Importantly, it has been found that EGCG combined with
tamoxifen significantly induced apoptosis and growth
inhibition in MDA-MB-231 human breast cancer
cells[42]. EGCG could also chemosensitize resistant tumor cells to
doxorubicin in the human carcinoma xenograft
model[43], suggesting its effects on cancer therapy in combination with
chemo-therapeutics.
COX-2 inhibitor NSAIDs have been shown to decrease
the risk of various cancers, including colon and lung
cancers[44,45]. NSAIDs exert apoptotic effects in a variety of
cancer cells, including esophageal, liver, colon, lung, oral,
and bladder cancer cells in a COX-2-dependent or
COX-2-independent manner through the regulation of other
molecules in cellular signaling
pathways[46]. Celecoxib, the first
selective COX-2 inhibitor approved for the
chemoprevention of colon cancer in patients with familial adenomatous
polyposis, has also been found to decrease the incidence of
various cancers in various animal models with
no associated toxicity[47]. Interestingly, the forced expression of COX-2
caused enhancement in multiple drug resistance (MDR)1
expression and functional activity, suggesting the existence
of a causal link between COX-2 activity and MDR1
expression[48]. Therefore, the use of COX-2 inhibitors to decrease
MDR1 function may enhance the accumulation of
chemotherapy agents and decrease the resistance of tumors to
chemotherapeutic drugs. Altorki et al found that celecoxib
enhanced the response to paclitaxel and carboplatin in
early-stage, non-small-cell lung
cancer[49]. Moreover, selective COX-2 inhibitors were found to enhance tumor response to
radiotherapy or radiochemotherapy, suggesting that these
agents can improve the response of various cancers to
conventional cancer therapies[50_52].
Resveratrol is a phytoalexin mainly found in grapes. It
exhibits anticancer properties in a variety of cancer cells
in vitro, including lymphoid, myeloid, breast, prostate, and
colon cancers[53]. Importantly, resveratrol has been reported
to sensitize non-Hodgkin's lymphoma and multiple myeloma
cells to paclitaxel-mediated
apoptosis[54]. The oral administration of proanthocyanidin, another compound from grapes,
has also been found to decrease the tumor progression and
the size of cutaneous carcinomas in an animal
study[55]. Another murine study showed that the administration of
grape seed extract significantly reduced metastatic melanoma
pulmonary nodules[56]. Moreover, proanthocyanidin has
been found to enhance doxorubicin-induced antitumor
effects and reverse drug resistance in doxorubicin-resistant
K562/DOX cells, breast cancer cells, and mouse tumor
xenograft models[57,58].
We and others have found that I3C from
cruciferous vegetables combined with cisplatin or tamoxifen could inhibit
the growth of PC-3 prostate and MCF-7 breast cancer cells
more effectively than either agent
alone[59,60]. Phenethyl-ITC (PEITC) is another compound from
cruciferous vegetables and has generated
a great deal of research interest due to its cancer
chemopreventive activity. PEITC administration
was shown to significantly inhibit carcinogen-induced oncogenesis in mouse
models[61_63]. More impor-tantly, PEITC has been found to inhibit angiogenesis
in vitro and ex vivo, suggesting that it is not just a chemopreventive
agent, but could also be used for cancer
therapy[64]. Recent reports showed that sulforaphane, another compound from
cruciferous vegetables, exerted its antiproliferative activity
in Akt-overexpressing ovarian cancer
cells[65]. These findings suggest the beneficial effects of
cruciferous vegetables in the fight against cancer.
Vitamin D obtained from the diet and synthesized in the
skin in response to UVB exposure has been advocated as a
potential preventive agent for prostate, colon, and lung
cancers[66_68]. Analogs of vitamin D were also shown to
potentiate the antiproliferative effect of doxorubicin, cisplatin, and
genistein in vitro[69].
N-(4-hydroxyphenyl) retinamide (4HPR;
fenretinide), a synthetic derivative of retinoic acid,
has been found to exert potent pro-apoptotic
effects on a variety of cancer
cells[70]. A recent report showed that 4HPR
combined with low doses of celecoxib more potently
inhibited growth and induced the apoptosis of premalignant and
tumorigenic bronchial epithelial cell
lines[71].
These reports clearly demonstrate that chemopreventive
agents (natural or synthetic agents, which inhibit the
development of cancer) could be used in cancer treatment to
further enhance the antitumor activities of conventional
chemotherapeutics (which have been used in the treatment of
cancer in clinics) and radiotherapy.
Targeting cellular signaling pathways by chemopreventive agents in cancer
preven-tion and treatment
In this review, we present a succinct summary of the
major signaling pathways that are regulated by
chemopre-ventive agents. It has been known that chemopreventive
agents exert their inhibitory effects on carcinogenesis
through multiple signaling pathways, including Akt,
NF-κB, mitogen-activated protein kinase (MAPK), p53, COX-2, Ras,
and many other molecules that are known to regulate cell
growth and apoptotic pathways. However, the molecular
mechanisms by which chemopreventive agents potentiate
the antitumor effects of cancer therapies have not been fully
elucidated. It is known that chemotherapy and radiotherapy
can induce drug resistance in cancer cells, resulting in
treatment failure. Emerging evidence has demonstrated that
MDR, NF-κB, Akt, and some molecules in the apoptotic
pathway are involved in the development of drug resistance.
Chemopreventive agents could sensitize cancer cells to
cancer therapies through the regulation of Akt, c-Myc,
NF-κB, COX-2, and apoptotic pathways, all of which are known to
play important roles in the regulation of cell survival and cell
growth (Figure 1).
Regulation of the Akt pathway It has been well known
that the Akt signaling pathway plays important roles in the
control of cell survival. Many chemopreventive agents have
been found to inhibit cancer cell growth and induce apoptosis
through the inhibition of the Akt
pathway[72]. A component of green tea, EGCG, promoted apoptosis in T24 human
bladder cancer cells via the modulation of the PI3K/Akt pathway
and Bcl-2 family proteins[73]. Indomethacin, a NSAID, has
been found to induce apoptosis in renal cell carcinoma cells
by activating Akt and MAPK
signaling[46]. Other COX-2 inhibitors, including celecoxib and SC236, have also been
found to inhibit cell growth and induce apop-tosis through
the regulation of Akt and the COX-2 signaling
pathway[70,74]. It has been known that the PEITC-mediated inhibition of the
angiogenic features of human umbilical vein endothelial cells
in vitro is associated with the inactivation of Akt, the
suppression of vascular endothelial growth factor (VEGF)
secretion, and the downregulation of VEGF receptor 2
protein levels[64]. In a study on sulforaphane from
cruciferous vegetables, PI3K and both total Akt protein and active
phosphorylated Akt (Ser473) were significantly decreased in
sulforaphane-treated ovarian cancer cells, suggesting the
inhibitory effect of sulforaphane on the Akt
pathway[65]. Deguelin, a member of the flavonoid family
with chemopre-ventive activities, has been found to decrease tumor
incidence in animal models for lung, colon, mammary, and skin
carcinogenesis through Akt
inhibition[75,76]. We and others have found that isoflavone genistein could inhibit cancer
cell growth and induce apoptosis through the downregulation
of Akt. These results demonstrate that Akt is a target of
chemopreventive agents in cancer prevention.
Growing evidence has also shown that activated Akt is
critical for acquiring drug
resistance[77_79], therefore the downregulation of Akt by chemopreventive agents could
sensitize cancer cells to chemotherapeutics or radiotherapy.
We and other investigators have found that activated Akt
was inhibited by isoflavone genistein combined with
gemcitabine or radiation in pancreatic, cervical, and
esophageal cancer cells, suggesting that the enhancement of
chemotherapeutic or radiation effects by isoflavone genistein
may be partially mediated by the inhibition of Akt
signaling[6,26,27]. It has been found that genistein also
enhanced necrotic-like cell death with the significant inhibition
of Akt activity in breast cancer cells treated with genis-tein
and adriamycin, suggesting that the enhanced growth
inhibition by combination treatment is through the inactivation
of the Akt pathway[19]. Kamsteeg et
al reported that phenoxo-diol, one of the synthetic derivatives of genistein, could
inhibit Akt signaling transduction and subsequently activate
the caspase system, inhibiting X-linked inhibitor of apoptosis
protein (XIAP) and in turn leading to increased
chemosen-sitization[14]. It has been reported that curcumin
downregul-ated the Taxol-induced phosphorylation of Akt, which
interacts with NF-κB, suggesting that enhanced antitumor
activity by curcumin is through the inactivation of the Akt and
NF-κB pathways[9].
Regulation of the c-Myc/cyclin D/CDK pathway
It is known that activated Akt can upregulate c-Myc through
the activation of IkappaB kinase complex
(IKK)/NF-κB and the inhibition of cyclin D1 and c-Myc
proteolysis[80,81]. Almost all types of human cancers show high frequencies
of c-Myc amplification or overexpression of its protein
product, c-Myc. c-Myc can induce cyclin D1 which
interacts with CDK4 and CDK6 to promote cell cycle
progression[82,83]. It has been found that curcumin inhibited the
expression of c-Myc and
tumorigenesis[84,85]. Other chemo-preventive agents, including EGCG, also showed their
ability to downregulate c-Myc[86,87]. It has been reported that
chemotherapeutics, including cisplatin, doxorubicin,
paclitaxel, and 5-FU can induce c-Myc
expression[88]. Interes-tingly, the surviving cancer cells from cisplatin treatment
display a significant elevation in c-Myc
expression[89] and the enhanced antitumor activity of chemotherapeutics can
be achieved by the combination treatment with low-dose
c-Myc antisense oligonucleotides[90], suggesting that c-Myc
could cause chemoresistance of cancer cells to
chemothera-peutics. Experimental studies have also shown that the
overexpression of cyclin D1 contributed to the
chemoresistance of pancreatic cancer cells because of the dual roles of
cyclin D1 in promoting cell proliferation and inhibiting
drug-induced apoptosis[91]. Therefore, the chemopreventive agent,
which downregulates c-Myc, cyclin D, and CDK, could be
used in combination with chemotherapeutics to improve the
treatment outcome in cancer therapy. It has been reported
that the combination of I3C and tamoxifen caused a more
pronounced decrease in CDK2-specific enzymatic activity,
CDK6 expression, and the level of phosphorylated
retinoblastoma protein, leading to the more effective inhibition of
the growth of human MCF-7 breast cancer cells compared to
either agent alone[59].
Regulation of the NF-κB pathway NF-κB is an inducible
and ubiquitously expressed transcription factor which
regulates cell survival, inflammation, and
differentiation[92]. It is becoming increasingly clear that
NF-κB signaling plays critical roles in cancer development and progression. A
large portion of cancer cells, especially poorly differentiated
cancer cells, shows activated NF-κB in the nucleus,
suggesting that activated NF-κB regulates its downstream genes
to promote cancer cell growth. Therefore, NF-κB has long
been believed to be a target for the prevention and treatment
of cancer. Several natural and synthetic chemopreventive
agents that are able to inhibit the activation of
NF-κB have been shown to either prevent cancer or to inhibit cell growth
in animal models[93]. It has been reported that curcumin
inhibited IKK, suppressed both constitutive and inducible
NF-κB activation, and potentiated tumor necrosis factor
(TNF)-induced apoptosis[94]. EGCG was also shown to
inhibit the activation of IKK, the phosphorylation of
IκBα, and the activation of NF-κB[95]. It has been found that
deguelin, a member of the flavonoid family, also exerted its
chemopreventive effects through the inhibition of
NF-κB activity, even in the presence of inflammatory stimuli, such
as TNF-α[96]. Other preventive agents, such as
Ganoderma lucidum from an oriental medical mushroom and silibinin from
the seeds of milk thistle, also inhibited cell growth and
induced apoptosis through the inhibition of the
NF-κB pathway[97,98]. We and others have reported that isoflavone
genistein significantly inhibited cancer cell growth and
induced apoptosis through the downregulation of
NF-κB activity[99,100]. We also found that DIM from
cruciferous vegetables inhibited NF-κB and its downstream genes VEGF,
urokinase-plasminogen activator (uPA), and matrix
metallo-proteinase (MMP)-9, leading to the inhibition of
angio-genesis, invasion, and metastasis in prostate cancer
cells[101]. These results demonstrate that
NF-κB is a target of chemopre-ventive agents in cancer prevention.
More importantly, it has been well known that many
chemotherapeutic agents induce the activity of
NF-κB, which causes drug resistance in cancer
cells[102]. Therefore, targeting NF-κB by chemopreventive agents could be a promising
strategy to enhance the antitumor activity of
chemotherapeutics in cancer treatment. From in
vitro and in vivo experimental studies, we observed that
NF-κB activity was significantly increased by cisplatin, docetaxel, gemcitabine, and
radiation treatment and that the NF-κB-inducing activity of
these agents was completely abrogated by isoflavone
genistein treatment in prostate, breast, lung, and pancreatic
cancer cells, suggesting that isoflavone genistein
pretreatment inactivates NF-κB and thus contributes to increased
growth inhibition and apoptosis induced by these
agents[6,7,12,24,103]. We also found that isoflavone genistein
enhanced the antitumor activity of CHOP by the inhibition
of NF-κB in lymphoma cells[18], suggesting that the
inhibition of NF-κB is the most important event for
chemosensitiza-tion. Studies also showed that increased cell death by
genistein and radiation occurred via the inhibition of
NF-κB, leading to the altered expression of regulatory cell cycle
proteins, cyclin B and p21WAF1/Cip1, thus promoting
G2/M
arrest and increased
radiosensitivity[103]. Similarly, curcumin
has been found to inhibit the activity of NF-κB, resulting in
the sensitization of cancer cells to cisplatin or Taxol-induced
apoptosis[9,104], suggesting its beneficial effects in cancer
treatment.
Regulation of the COX-2 pathway COX plays an
important role in the biosynthesis of prostanoids. COX-1 is
constitutively expressed in many tissues and is involved in
the housekeeping function of prostanoids, while COX-2,
the inducible isoform, accounts for the elevated
production of prostaglandins in response to various inflammatory
stimuli, hormones, and growth factors. COX-2 has received
more attention than COX-1 in cancer research because
COX-2 expression is associated with cell growth regulation,
tissue remodeling, and carcinogenesis. In recent years,
COX-2 inhibitors and NSAIDs have been shown to decrease the
risk of various cancers, including colon and lung cancers,
suggesting that the downregulation of COX-2 could be one
of the molecular mechanisms by which chemopreventive
agents prevent and inhibit tumor growth. It has been found
that curcumin or EGCG inhibited the expression of COX-2
along with the growth of colorectal or prostate cancer
cells[35,105]. Experimental studies have also shown that
curcumin and EGCG could downregulate COX-2 expression
without any change in the expression of COX-1 at both the
mRNA and protein levels in colorectal or prostate cancer
cells, suggesting that a combination of chemopreventive
agent, such as curcumin or EGCG, with chemotherapeutic
agents could be an improved strategy for the treatment of
colorectal or prostate cancer[35,105]. In support of this
sug-gestion, the synergistic growth inhibitory effect of curcumin
and celecoxib has been demonstrated in colorectal cancer
cells through the inhibition of the COX-2
pathway[35]. The combination of 5-FU and isoflavone genistein also enhanced
therapeutic effects in colon cancer through the COX-2
pathway[13], although the inhibition of tumor growth by some
COX-2 inhibitors could also be mediated through the
COX-2-independent pathway. Studies have
shown that celecoxib at clinically feasible concentrations
(£5.6 µmol/L) markedly suppresses the biosynthesis of
prostaglandin E2 (PGE2) in
COX-2-expressing lung cancer
cells[106]. However, much higher
doses of celecoxib (³25 µmol/L) are required for
growth inhibition and apoptosis induction in cell culture
systems, suggesting its COX-2-independent
activity[107]. A recent report also showed that even at a low concentration,
celecoxib combined with 4HPR inhibited cell growth and
induced apoptosis though COX-2-independent mecha-
nisms[70], and as such, suggest that further studies are needed
to fully elucidate the mechanism of action of COX-2
inhibitors toward cancer prevention and therapy.
Regulation of the apoptotic pathway It has been well
known that Akt, c-Myc, NF-κB, and COX-2 signaling could
mediate apoptotic processes through the regulation of
molecules in the apoptotic pathway. Therefore, the regulation
of these signaling molecules by chemopreventive agents
could lead to alterations in the levels of important molecules
in the apoptotic pathway. EGCG, which inhibits Akt and
NF-κB signaling, has been found to promote apoptosis in
T24 human bladder cancer cells via the modulation of
proteins in the Bcl-2 family[73]. It has also been reported that the
genistein derivative phenoxodiol can bind to the tumor-associated NOX (tNOX) receptor, block its function, and
subsequently inhibit the anti-apoptotic proteins XIAP and
FADD-like ICE (FLICE) inhibitory protein, eventually
inducing apoptotic cell death[14]. We and others have also found
that isoflavone genistein combined with docetaxel or
gemcitabine significantly inhibited Bcl-2,
Bcl-XL, and survivin, and induced
p21WAF1, suggesting that the enhanced antitumor effect in combination treatment is through the
regulation of these important molecules in the apoptotic
pathway[6,7]. It has been found that curcumin combined with
cisplatin decreased the expression of several apoptosis-related genes, including c-Myc, Bcl-XL, c-IAP-2, neuronal
apoptosiainhibitory protein (NAIP), and
XIAP[8]. The combination of curcumin and TRAIL also induced the cleavage
of procaspase-3, procaspase-8, and procaspase-9, the
truncation of Bid, and the release of cytochrome c from the
mitochondria in prostate cancer cells, indicating that the apoptotic
pathway is triggered in prostate cancer cells treated with a
combination of curcumin and TRAIL[36]. These findings
suggest that chemopreventive agents also regulate the apoptotic
pathway during cancer prevention and treatment.
Regulation of other pathways We have reported that the
antitumor and antimetastatic activities of docetaxel are
enhanced by isoflavone genistein through the regulation of
osteoprotegerin/receptor activator of NF-κB (RANK)/RANK
ligand/MMP-9 signaling in prostate cancer, suggesting that
isoflavone genistein could be a promising non-toxic agent
to improve the treatment outcome of metastatic prostate
cancer with docetaxel[11]. Soy isoflavone also enhanced
prostate cancer radiotherapy through the downregulation of
apurinic/apyrimidinic endonuclease 1/redox factor-1
expression[108]. In addition, isoflavone genistein and its isoflavone
analogs also showed the potential to decrease the side-effects of tamoxifen through metabolic interactions that
inhibit the formation of α-hydroxytamoxifen via the
inhibition of CYP1A2[109], resulting in the beneficial effects of
isoflavone genistein in combination with tamoxifen.
It has been found that phenoxodiol, another analog of
isoflavone, exerts its inhibitory effects on cancer through
pleiotropic molecular mechanisms. In addition to the
regulation of Akt and the caspase-dependent apoptotic pathway,
phenoxodiol also induced G1 arrest by specific loss in
cyclin-dependent kinase 2 activity through the p53-independent
induction of p21WAF1/CIP1 [110]. In addition, phenoxodiol also
inhibits the catalytic activity of topo II in a dose-dependent
manner and stabilizes the topo II-mediated cleavable
complex[111], demonstrating the pleiotropic effects of this agent
in cancer prevention and treatment. The enhanced effects
of chemotherapy by chemopreventive agents may also be
related to immunopotentiating activities through the
reduction of interleukin (IL)-6[10] and the enhancements of
lymphocyte proliferation, NK cell cytotoxicity, the CD4+/CD8+
ratio, IL-2, and interferon (IFN)-g
productions[57]. These results clearly suggest that chemopreventive agents are
pleiotropic and thus could be considered as multitarget agents
that are likely to revolutionize our approach for the
prevention and treatment of cancer.
Conclusion and perspective
The emerging evidence from in vitro and
in vivo studies reviewed above demonstrate that chemopreventive agents
could inhibit the development and progression of cancer by
targeting multiple cell signaling pathways for cancer
prevention and treatment. It is important to note that one
chemopreventive agent could target several cell signaling
pathways which crosstalk in a complex cellular signal
transduction network that are responsible for the development
and progression of cancer. Further in-depth mechanistic
studies, in vivo animal experiments, and novel clinical trials
are needed to investigate the effects of chemopreventive
agents in the combination treatment of cancer with
conventional cancer therapies. Moreover, further development of
potent natural and synthetic chemopreventive agents are
also needed to improve the efficacy of mechanism-based
and targeted therapeutic strategies to win the battle against
cancer.
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