Jiang, Z., Chen, K., Cheng, L., Yan, B., Qian, W., Cao, J., ... Yang, W. (2017) - Resveratrol y Tratamiento Del Cáncer - Actualizaciones.
Jiang, Z., Chen, K., Cheng, L., Yan, B., Qian, W., Cao, J., ... Yang, W. (2017) - Resveratrol y Tratamiento Del Cáncer - Actualizaciones.
Jiang, Z., Chen, K., Cheng, L., Yan, B., Qian, W., Cao, J., ... Yang, W. (2017) - Resveratrol y Tratamiento Del Cáncer - Actualizaciones.
ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S
Issue: Resveratrol and Health
CONCISE REVIEW
Address for correspondence: Wei Yang and Qingyong Ma, Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi’an
Jiaotong University, 277 West Yanta Road, Xi’an 710061, China. [email protected]
Cancer, a growing health problem worldwide, affects millions of people every year. The overall survival rates of most
cancers have been prolonged owing to the efforts of clinicians and scientists. However, some tumors develop resistance
to chemoradiotherapeutic agents, and the cancer research community continues to search for effective sensitizers.
Resveratrol, a natural polyphenolic phytoalexin, has shown promising effects in inhibiting proliferation and cancer
progression in several tumor models. However, its molecular mechanisms and applications in chemotherapy and
radiotherapy have yet to be fully determined. In this concise review, we highlight the role and related molecular
mechanisms of resveratrol in cancer treatment. In particular, we focus on the role of resveratrol in the tumor
microenvironment and the sensitization of cancer cells for chemotherapy and radiotherapy. Resveratrol shows
promising efficacies in cancer treatment and may be applied in clinical therapy, but it requires further clinical study.
Keywords: resveratrol; cancer therapy; tumor microenvironment; cancer stem cells; chemoradiosensitization
Over the past several years, numerous studies have signaling pathways to induce human diffuse large B
demonstrated that resveratrol can directly inhibit cell lymphoma cell apoptosis in vivo and in vitro.9
the proliferation and viability of cancer cells in a This may explain why combinations of resveratrol
dose- and time-dependent manner in vitro, and and other chemotherapy drugs showed better
many reports have demonstrated that resveratrol anticancer effects. Vendrely et al. reported that ROS
could be used as a cancer chemopreventive agent production was exacerbated after treatment with
owing to its ability to induce growth inhibition, resveratrol analogues and capsaicin in pancreatic
cell cycle arrest, and apoptosis in several human adenocarcinoma, which resulted in activation of
cancer cell lines.4,5 Although resveratrol has shown the p38 MAPK pathway and disrupted the balance
many anticancer effects, the mechanisms by which of Bcl-2 and BAX expression, leading to apoptosis.5
it exerts these effects are not yet fully understood. In Kim et al. also found that capsaicin and resveratrol,
this paper, we will review recent advances in the use alone or in combination, induced cell apoptosis
of resveratrol and its analogs in cancer treatment, and inhibited cell growth through upregulating NO
focusing on the role of resveratrol in the tumor production and Bax expression, accompanied by a
microenvironment and in sensitization of cancer reduction of MDM2, Bcl-2, cytochrome c expression
cells for chemotherapy and radiotherapy and its rel- and activation of caspase-9, caspase-3, caspase-8,
ative mechanisms and future applications. death receptor 4, and Fas (CD95), suggesting that
capsaicin and resveratrol induce cell apoptosis
Resveratrol regulates the level of reactive
through activation of the mitochondrial and death
oxygen species
receptor pathways together.10
Reactive oxygen species (ROS), including hydrogen
The main molecular mechanisms of
peroxide (H2 O2 ), hypochlorous acid (HOCl), and
resveratrol in killing tumor cells
free radicals (e.g., hydroxyl radical (• OH), superox-
ide anion (• O2– ), and lipid peroxides), can damage The antitumor effect of resveratrol depends on
nucleic acids, lipids, and proteins.6 It has been the type and status of cancer cells, and this effect
demonstrated that most malignant tumor cells have depends on the dose of resveratrol. For most tumor
increased levels of ROS, which play an important cells, resveratrol can induce apoptosis and cell cycle
role in the initiation and progression of cancer by arrest. However, for neuronal cells or endothelial
promoting cell proliferation, survival, invasion, and cells suffering severe oxidative stress, resveratrol
metastasis.5,7 Resveratrol has antioxidant properties can also help them avoid radiation damage and
through modulating antioxidant enzyme activity, cytotoxic drug stimulation by reducing oxidative
which likely contributes to its anticancer effects. stress and upregulating the expression of survival
Mechanistically, resveratrol can upregulate super- proteins.11 As a result, resveratrol can be used in
oxide dismutase (SOD), catalase, and glutathione chemotherapy to protect normal cells to reduce
peroxidase expression and their enzymatic activity adverse effects owing to this property. In general,
in tumor cells, which leads to mitochondrial the specific molecular mechanisms and signaling
accumulation of H2 O2 and ultimately induced pathways involved in the antitumor effect of
cancer cell apoptosis. On the other hand, slight resveratrol include (1) regulation of mitochondrial
upregulation of antioxidative enzymes and reducing and caspase cascade enzymatic system activation;
oxidative stress could explain the protective effect of (2) upregulation of cyclin-dependent kinase
resveratrol on normal cells. Jung et al. demonstrated inhibitors, tumor suppressor genes, death-induced
that resveratrol can inhibit the level of intracellular cytokines, and their receptors; (3) downregulation
ROS and downregulate hypoxia-inducible factor- of the expression of survival proteins associated
1␣ (HIF-1␣) accumulation, thus suppressing lung with the development of chemoresistance, includ-
cancer, colon cancer, and breast cancer cell 18 F-FDG ing survivin, cFLIP, cIAPs, and antiapoptotic
uptake and glycolytic metabolism.8 Kong et al. proteins (Bcl-2 and Bcl-XL);12 (4) activation of
found that pterostilbene, a natural dimethylated adenosine 5 -monophosphate–activated protein
analog of resveratrol, could increase ROS levels kinase (AMPK), and (5) inhibition of MAPK,
via suppression of ERK1/2 and activation of phosphoinositide 3-kinase (PI3K)/Akt,13 hedgehog
p38 mitogen-activated protein kinase (MAPK) (HH),14 hippo–YAP,15 PKC, EGFR kinase, nuclear
Figure 1. The signaling pathways by which resveratrol suppresses the malignant biological behaviors of cancer cells, including
proliferation, antiapoptosis, invasion, migration, EMT progress, levels of ROS, and stemness.
factor B (NF-B), activating protein-1 (AP-1),16 fore, as an effective antitumor bioactive substance,
HIF-1␣,17 and signal transducer and activator resveratrol can modulate the tumor microenviron-
of transcription 3 (STAT3).18 However, the exact ment via multiple pathways (Fig. 1).
molecular mechanisms need further investigation. Desmoplasia, a dominant characteristic of the
pancreatic ductal adenocarcinoma (PDAC) tumor
The role of resveratrol in the tumor microenvironment, is induced by activation of pan-
microenvironment creatic stellate cells (PSCs), which synthesize and
The tumor microenvironment is a complex environ- secrete large amounts of ECM, as well as other fac-
ment containing various cellular components (e.g., tors, such as cytokines and growth factors, which
stromal cells, immune cells, and vascular endothe- can promote fibrosis and accelerate tumor growth.20
lial cells), multitudinous factors (e.g., cytokines), Tsang et al.21 and Lin et al.22 demonstrated that
abundant extracellular matrix (ECM), and their var- resveratrol can suppress the activation of PSCs,
ious cross talk networks; in other words, intercel- and the suppressive effects are associated with a
lular or extracellular interaction networks in the decrease in NF-B activation and Akt phosphoryla-
tumor microenvironment usually play vital roles tion. The activated PSCs exhibit tumor-promoting
in both tumor initiation and progression. Specif- effects via complicated interactions with pancre-
ically, the formation and progression of the cancer atic cancer cells and other cellular or noncellular
cell, as well as metastasis and chemoresistance, are components, as well as the fibrosis in PDAC tumor
related to the tumor microenvironment. For exam- microenvironments. We speculated that PSCs or
ple, tumor cells and inflammatory cells can produce other cancer-associated fibroblasts (CAFs) may have
some cytokines, like tumor necrosis factor (TNF)- a marked influence on promoting cancer cell pro-
␣, which can promote tumor malignant progres- liferation and invasion through PDGF/PDGFR,
sion through the induction of NF-B–dependent stromal-derived factor-1/CXCR4, the IGF-1/IGF1R
antiapoptotic molecules.19 In other words, effective signaling pathway, and MMP-2/9 secretion, and
methods of modulating the tumor microenviron- these promotion effects could be reversed by resver-
ment could be a new mode of cancer therapy. There- atrol treatment.23–25
In addition, another prominent characteristic of cell cycle progression. Resveratrol suppressed the
the tumor microenvironment is increased levels of activity of T and B cells and macrophages via the
immune or inflammation-related cells and factors, following mechanisms: inhibition of proliferation
such as lymph cells, granulocytes, macrophages, of T cells and secretion of IFN-␥ and IL-4, sup-
cytokines, and adhesion molecules. For instance, pression of proliferation of B cells and production
it has been proved clearly that at least 25% of of IgG1 and IgG2a isotypes, suppression of proin-
malignant tumors are induced or worsened by flammatory cytokines (IL-1, IL-6, and TNF-␣) but
an inflammatory environment. Inflammation, in upregulation of anti-inflammatory cytokine IL-10,
particular chronic inflammation, has been shown and downregulation of expression of CD28 on
to play a crucial role in infection, diabetes mellitus, CD4+ T cells and CD80 on macrophages.30 Taken
and cancer.26 Although the mechanisms of these are together, these data suggest that resveratrol may be
still not yet clear, we can hypothesize that intricate used to modulate the immunological reaction in
inflammatory or immunological reaction in local tumor microenvironment.
tumor microenvironments, as well as throughout Tang et al.31 demonstrated that resveratrol
the body, has key roles in tumor development. induced nuclear accumulation of COX-2 and
During these processes, inflammation or immunity facilitates p53-dependent apoptosis in human
results from complex responses that involve many breast cancer cells. Additionally, tumor vessels and
molecular and cellular events and the intricate vascular endothelial cells are one of the most essen-
interactions among innate and adaptive cells, such tial parts of tumor microenvironment. Folkman32
as lymphocytes, dendritic cells, and macrophages, first presented the hypothesis that tumor growth
as well as cytokines secreted by them or other depends on angiogenesis in 1971. From then on,
nonimmune cells (e.g., cancer cells or vascular accumulating data have revealed that angiogenesis
endothelial cells) in the tumor microenvironment as facilitates tumor progression via delivering oxygen
a consequence of cell–cell interactions.27 Accumu- and nutrients to cancer cells and other cells in
lating evidence indicates that resveratrol may play the tumor microenvironment, exacerbating tumor
an important anti-inflammatory role in the tumor local invasion or metastasis and increasing various
microenvironment. One of the possible mecha- immune or inflammatory elements (e.g., cytokines,
nisms for its protective activities is downregulation IL-1, VEGF, and MMPs), CAFs, and other cellular
of inflammatory responses, including inhibition of or noncellular elements, which further contribute
synthesis and release of proinflammatory mediators, to tumor progression, metastasis, and chemore-
such as IL-1, IL-6, and TNF-␣,28 and increased sistance when they infiltrate into the tumor
expression of anti-inflammatory factors like IL-10,29 microenvironment.33–35 Hence, angiogenesis in the
modification of eicosanoid synthesis, or inhibition tumor microenvironment is becoming a promising
of enzymes, such as cyclooxygenase-1 (COX-1) or therapeutic target in cancer therapy, and Garvin
COX-2, which are responsible for the synthesis of et al.36 demonstrated that resveratrol can inhibit
proinflammatory mediators through the inhibitory tumor angiogenesis in breast cancer xenografts. Fur-
effects of resveratrol on transcription factors like thermore, Bishayee et al.37 showed that resveratrol
NF-B or AP-1. Moreover, resveratrol also showed impaired VEGF expression through downregula-
an ability to inhibit some activated immune cells, tion of HIF-1␣, which may reduce angiogenesis
such as T cells, B cells, and macrophages through the during hepatocarcinogenesis. More directly, resver-
CD28/CTLA-4 and CD80 costimulatory pathway.30 atrol can play an efficient role in antiangiogenesis
CD28 is expressed on resting T cells and can be by affecting the growth of capillary endothe-
engaged by either CD80 or CD86 on antigen- lial cells in vitro and new blood vessels growth
presenting cells (APCs), leading to the activation in vivo.38
of resting T cells. This costimulation leads T cells In conclusion, resveratrol plays a significant role
to increase the production of growth factor and in the treatment of cancer through modulating
increase cell survival signals. CD28 and CTLA-4 are the tumor microenvironment via several modes
both expressed on activated T cells. Engagement (Fig. 2) for which the specific mechanisms still need
of CTLA-4 on CD80 or CD86 on APCs decreases to be determined. Well-designed clinical trials are
T cell proliferation, growth factor production, and urgently needed as well.
Figure 2. The effects of resveratrol on the tumor microenvironment. The tumor microenvironment consists of various cellular
components (e.g., fibroblasts, immune cells, and vascular endothelial cells), multitudinous factors (e.g., cytokines), and abundant
ECM. Resveratrol suppresses the activation of cancer-associated fibroblasts by inhibiting the NF-B and AKT pathway to inhibit the
proliferation, invasion, migration, and chemoresistance of cancer cells. Resveratrol exhibits anti-inflammatory activity by inhibiting
COX-2, the core of inflammation, and decreasing the secretion of proinflammatory factors, such as IL-1, IL-6, and TNF-␣, and
increasing anti-inflammatory factors like IL-10, inhibition of transcriptional factor NF-B or AP-1, and inhibition of activated
immune cells, such as T cells, B cells, and macrophages. Resveratrol impairs VEGF expression through downregulation of HIF-1␣,
and this may cause a reduction of angiogenesis.
resistance to cell death via phosphorylation of Akt and metastasis by giving rise to new tumors, and
and activation of Bad; MAPK signaling pathway add a new level of complexity to therapeutic failure.
(ERK, JNK, and P38) phosphorylation; and AP-1, Conventional chemotherapies usually kill differen-
Bcl-2, and XIAP upregulation, which can be signifi- tiated or differentiating cells that constitute most
cantly inhibited by resveratrol. These results demon- of the tumor and do not generate new cells, while a
strate that resveratrol could serve as a chemosensi- population of CSCs could survive and cause relapse.
tizer in docetaxel chemotherapy by targeting HER2 CSCs play an important role in various prosurvival
and blocking its downstream signaling pathways, mechanisms against chemotherapy, such as elevated
such as the Akt and MAPK pathways.47 Resveratrol apoptosis resistance, DNA repair efficiency, drug-
prevents epithelial–mesenchymal transition (EMT) efflux pumps, detoxification enzyme expression,
of gastric cancer and functions as a novel sensitizer and quiescence.53 Therefore, development of spe-
to reverse docetaxel resistance via the PTEN/Akt cific therapies targeting CSCs could improve cancer
signaling pathway. Docetaxel–resveratrol combined patients’ survival time and quality of life, especially
treatment provides a promising future for gastric for patients with distant metastasis. Resveratrol may
cancer patients to postpone drug resistance and sensitize CSCs to chemotherapy via suppressing
prolong survival.45 Resveratrol can induce S phase CSC self-renewal pathways, including the Wnt/-
arrest, and the combination of 5-fluorouracil and catenin, notch, and HH signaling pathway.54 Cell
resveratrol can induce cell apoptosis significantly viability, proliferation, and motility of glioma
through elevation of levels of cleaved poly(ADP- stem cells are inhibited after resveratrol treatment,
ribose) polymerase (PARP), activated caspase-3, which may function through modulating the Wnt
and p53 proteins and the Bax/Bcl-2 ratio.48 signaling pathway and its downstream molecules,
In many cancers, the cytotoxicity of chemother- such as c-Myc and -catenin. In the meantime,
apeutic agents is largely attributed to induction TWIST1 and SNAIL1, two EMT markers, are
of cell apoptosis. However, it has been widely downregulated.55 A combination of resveratrol and
acknowledged that aberrant NF-B activation grape seed extract induces apoptosis in colon CSCs
could induce cell proliferation, angiogenesis, and via elevated p53, cleaved PARP, and altered Bax/Bcl-
invasion/metastasis and is closely associated with 2 ratio.56 In breast CSCs, resveratrol significantly
chemoresistance.49 Moreover, NF-B activation reduced cell viability and mammosphere forma-
could upregulate the levels of some antiapoptotic tion, followed by induction of apoptosis in cancer
genes, including TNF receptor–associated factor stem-like cells. This inhibitory effect of resveratrol
1(TRAF1), TRAF2, Bcl-2 family members, c-IAP1, is accompanied by a significant reduction in lipid
and c-IAP.50 Elevated NF-B activity has also synthesis,which is caused by downregulation of the
been demonstrated to play a vital role in Kras- fatty acid synthase gene followed by upregulation
induced pancreatic cancer progression and to help of proapoptotic genes DAPK2 and BNIP3.57
tumor cells survive gemcitabine treatment.51,52
Resveratrol sensitizes cancer cells to
Resveratrol–temozolomide combined treatment
radiotherapy
reverses the chemoresistance of glioblastoma cells
by reducing NF-B activity and nuclear translo- Resveratrol enhances radiosensitivity and has syn-
cation, which can be abolished by recombinant ergistic antitumor effects both in vitro and in vivo.
NF-B subunit p65, suggesting that the underlying In general, combined resveratrol and ionizing radi-
mechanisms of NF-B are regulated by resveratrol ation cancer treatment significantly increases tumor
in chemosensitization.43 cell autophagy and apoptosis,58 reduces the repair
of DNA damage,59 causes premature senescence
Effects of resveratrol on cancer stem
partly via increasing DNA double-strand breaks,
cell–induced chemoresistance
and markedly upregulates ROS production, which
Cancer stem cells (CSCs) are a subgroup of cancer can be attenuated by the ROS scavenger N-acetyl-
cells that have characteristics associated with cysteine.60 Resveratrol functions as a radiation sen-
normal stem cells. CSCs may generate tumors sitizer in melanoma via decreasing cyclin B, cyclin D,
through the stem cell processes of self-renewal and Cdk2, and Cdk4 expression and inducing proapop-
differentiation into multiple cell types, cause relapse tosis effects mediated by FLIP, Bcl-2, and survivin
downregulation,61 and sensitizes nasopharyngeal cess through decreasing NF-B and PARP-1 expres-
cancer cells to ionizing radiation by inhibiting E2F1 sion, which led to the expression of inflammatory
and p-AKT in vitro. Furthermore, resveratrol com- markers, including IL-6, IL-8, and visfatin mRNA
bined with radiation therapy significantly reduces levels, as well as inducible nitric oxide synthase
tumor volume and weight compared with single and COX-2 protein expression with a concomitant
treatment in vivo62 and increases apoptosis and reduction in IL-10 mRNA levels.66 Another ani-
autophagy in glioma xenografts of a nude mouse mal study showed that radiation caused a reduc-
model.59 However, the combination therapy has lit- tion of saliva secretion, salivary amylase activity,
tle effect on p-AKT expression in prostate cancer, and SOD expression and an elevation of MDA in
whereas the expression of p-H2A.X, a marker for mice. Administration of resveratrol reversed the
senescence, is increased,63 indicating that different reduction of saliva secretion induced by irradia-
mechanisms are involved, despite similar synergis- tion and restored salivary amylase and SOD activ-
tic tumor-killing effects among numerous cancer ity. In addition, resveratrol inhibited increases in
types. transforming growth factor 1 expression induced
Apart from inducing the death of several cancer by radiation.67 This result showed that resvera-
cell lines synergistically with radiation, resveratrol trol may be used as a radioprotective agent to
may be used as a radioprotective agent to reduce reduce the adverse effects, including xerostomia and
the adverse effects induced by radiotherapy. Radia- mucositis, induced by radiotherapy. Furthermore,
tion damages cells via direct ionization of the atoms resveratrol reduced radiation-induced chromosome
within DNA and other cellular molecules and by aberration frequencies in mouse bone marrow
indirect effects mediated through free oxygen rad- cells.68 These results showed that resveratrol may
icals. Irradiation-associated ROS production, how- be used as a radioprotective agent before radiother-
ever, occurs not only in cancer cells, but also in apy. However, for therapy of radioresistant malig-
healthy tissues. Irradiation of healthy tissues dur- nant cells, the dose and content of resveratrol and
ing the course of therapeutic radiation can result in ionizing radiation should be applied meticulously
a range of side effects, including self-limited acute in order to achieve an appropriate therapeutic effect
toxicities, mild chronic symptoms, and severe organ with less toxicity to normal cells.
dysfunction, including xerostomia (dry mouth), Taken together, these data demonstrate that
mucositis, dental carries, difficulty swallowing, and resveratrol can be used as an anticancer drug for
eventually inadequate feeding. An animal study was patients that increases sensitivity to chemotherapy
carried out in rats that were exposed to total-body and radiotherapy and reduces adverse effects.
irradiation 24 h after the resveratrol treatment. The
The clinical applications of resveratrol
results showed that antioxidant glutathione levels
require further investigation
were significantly increased, and the tissue activities
of malondialdehyde (MDA) in both the parotid and Safety of resveratrol
submandibular glands were significantly reduced by In order to investigate the safety and pharmacoki-
high doses of resveratrol treatment (100 mg/kg).64 netics of resveratrol before its application in can-
Adhami et al.65 examined the mechanisms of cer prevention and therapy, 40 healthy volunteers
resveratrol-mediated protection of human skin ker- were recruited and divided into four groups that
atinocytes from the adverse effects of UVB radiation. ingested resveratrol at a dose of 0.5, 1.0, 2.5, or 5.0 g,
This study demonstrated that UVB (40 mJ/cm2 ) respectively, for 4 weeks (Table 1).69 Resveratrol was
exposure led to a significant activation of NF-B rapidly absorbed, and it yielded peak concentration
in normal human epidermal keratinocytes, whereas at nearly 1 h postingestion. The plasma elimina-
pretreatment with resveratrol resulted in a sig- tion half-life of resveratrol varied between 4.77 and
nificant dose- and time-dependent downmodula- 9.70 hours.69 The majority of adverse events were
tion of UVB-induced inhibitory B kinase/IB␣– mild gastrointestinal discomfort, including diar-
mediated NF-B activation. Resveratrol counter- rhea, nausea, flatulence, and abdominal discom-
acts ␥ -irradiation radiotherapy-induced premature fort, and were mainly reported in participants with
ovarian failure via activation of PPAR-␥ and SIRT1, higher doses of resveratrol (2.5 and 5.0 g).69 Weight
attenuating radiation-triggered inflammatory pro- loss was not observed in any of the participants, and
Table 1. Clinical trials of resveratrol in healthy volunteers or patients with malignant disease
Brown et al.69 To assess its safety and 40 healthy volunteers 0.5, 1.0, Resveratrol was safe, but the 2.5
pharmacokinetics 2.5, or and 5 g doses caused
5.0 g mild-to-moderate
gastrointestinal symptoms
Patel et al.70 To measure concentrations of 20 patients with 0.5 or 1.0 g Daily oral doses of resveratrol at
resveratrol and its histologically 0.5 or 1.0 g produce levels in
metabolites in colorectal confirmed the human gastrointestinal
tissue of humans who colorectal cancer tract of an order of magnitude
ingested resveratrol sufficient to elicit
anticarcinogenic effects
Howells et To assess the safety, 9 patients presenting 5.0 g SRT501 was found to be well
al.74 pharmacokinetics, and with confirmed tolerated, and it increased
pharmacodynamics of stage IV colorectal apoptosis in malignant hepatic
micronized resveratrol cancer and hepatic tissues
(SRT501) metastases
Zhu et al.71 To assess the effect of 39 adult women at 5 or 50 mg Resveratrol decreased the
resveratrol on DNA increased breast methylation of the tumor
methylation and cancer risk suppressor gene RASSF-1␣
prostaglandin expression in
humans
Chow et al.73 To determine the effect of 42 healthy volunteers 1.0 g Resveratrol can modulate enzyme
resveratrol on drug and systems involved in carcinogen
carcinogen metabolizing activation and detoxification,
enzymes which may be one mechanism
by which resveratrol inhibits
carcinogenesis
Popat et al.75 Phase II study of resveratrol 24 patients who had 5.0 g Resveratrol showed an
(SRT501) with bortezomib relapsed or were unacceptable safety profile and
for patients with relapsed refractory to at least minimal efficacy in patients
and/or refractory multiple one prior therapy with relapsed or refractory
myeloma multiple myeloma
all of them presented normal performance status tigate the cancer-preventive effects of resveratrol
during the study period.69 In order to investigate (Table 1). After intake of resveratrol or placebo daily
the safety of resveratrol, it was verified in patients for 12 weeks, mammary ductoscopy specimens from
with resectable colorectal cancer.70 Patients ingested all of the participants were collected and analyzed
0.5 or 1.0 g resveratrol daily for 8 days before surgery. for methylation of p16, CCND2, RASSF-1␣, and
Similar to the previous report,69 it was well tolerated APC. This study revealed that ingestion of resver-
in patients at doses of 0.5 or 1.0 g, and there were no atrol decreased methylation of RASSF-1␣,71 which
reported resveratrol-related adverse events.70 These is implicated in cell cycle regulation, apoptosis, and
data suggest that intake of resveratrol is relatively tumorigenesis.72 A previous clinical study suggested
safe, despite the incidence of mild-to-moderate gas- that resveratrol can modulate enzymes involved in
trointestinal discomfort. carcinogen activation and detoxification, and this
may be one of the mechanisms by which resveratrol
Resveratrol showed promising effects in inhibits carcinogenesis.73 In colorectal cancer,
cancer prevention and treatment resveratrol reduced immunostaining of Ki-67,
In order to verify the role of resveratrol in cancer which is exclusively expressed in proliferating cells
prevention and treatment, 39 adult women with and used as a maker of cell growth,70 and it pro-
increased breast cancer risk were recruited to inves- moted apoptosis, which was reflected by increased
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