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Cancer chemopreventive activity of resveratrol, a natural product
derived from grapes.
Resveratrol, a phytoalexin found in grapes and other food products, was purified
and shown to have cancer chemopreventive activity in assays representing three
major stages of carcinogenesis. Resveratrol was found to act as an antioxidant
and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation
activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase
and hydroperoxidase functions (antipromotion activity); and it induced human
promyelocytic leukemia cell differentiation (antiprogression activity). In addition,
it inhibited the development of preneoplastic lesions in carcinogen-treated mouse
mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer
model. These data suggest that resveratrol, a common constituent of the human
diet, merits investigation as a potential cancer chemopreventive agent in humans.
Science . 1997 Jan 10;275(5297):218-20
Resveratrol: a candidate nutritional substance for prostate
cancer prevention.
The dietary stilbene resveratrol is a major constituent of a variety of edible
plant products, including grapes and peanuts. Resveratrol has been identified
as an excellent candidate cancer chemopreventive, based on its safety and efficacy
in animal models of carcinogenesis. Resveratrol is a prototype of a plethora
of bioactive polyphenols in the food supply that has just begun to be mined
for cancer preventive agents. For example, polyphenolic grapeseed fractions
were shown recently to potently antagonize chemical carcinogenesis. Taking
into consideration that the identification of resveratrol as a cancer preventive
agent is largely owed to its high abundance in nature (e.g., it accounts for
5-10% of the grapeskin biomass), it is logical to expect that naturally occurring
stilbenes that are superior to resveratrol in their cancer preventive properties
await identification. Thus, resveratrol may represent the tip of the iceberg
of a broad class of stilbene and related polyphenolic natural products that
include safe and highly effective agents for cancer prevention. We hypothesize
that resveratrol may be especially suitable as a lead agent for prostate cancer
prevention given its ability to: 1) inhibit each stage of multistage carcinogenesis,
2) scavenge incipient populations of androgen-dependent prostate cancer cells
through androgen receptor antagonism, and 3) scavenge incipient populations
of androgen-independent prostate cancer cells by short-circuiting the epidermal
growth factor-receptor (EGFR)-dependent autocrine loops in the cancer cells.
J Nutr . 2003 Jul;133(7 Suppl):2440S-2443S
Inhibition of NF-kappaB pathway in grape seed extract-induced
apoptotic death of human prostate carcinoma DU145 cells.
The alarmingly high rate of prostate cancer (PCA) mortality as well
as the limited success in the treatment of advanced PCA suggest that
additional approaches are needed to control PCA growth and its metastatic
potential. A constitutive activation of NF-kappaB family of transcription
factors is known to play a major role in chemotherapy resistance in
advanced PCA. In recent studies we showed that grape seed extract
(GSE) inhibits advanced human PCA growth and induces apoptosis in
cell culture and in nude mice. Accordingly, here we assessed the effect
of GSE on constitutive and TNFalpha-induced NF-kappaB DNA binding
activity and apoptotic death in advanced human prostate carcinoma
DU145 cells. Constitutive and TNFalpha-induced NF-kappaB DNA binding
activity was inhibited by GSE at doses > or =50 microg/ml and treatments for > or =12 h. This
was accompanied by inhibition of IkappaBalpha phosphorylation and IKKalpha
kinase activity. A strong induction of apoptosis (P<0.01) was also observed
following GSE treatment, while a combination with TNFalpha strongly potentiated
apoptosis induction. Our results indicate the potential of developing GSE as
an effective cancer therapeutic agent, both alone and in combination with TNFalpha-based
chemotherapy of advanced human prostate carcinoma that might prove to be a
more effective and less toxic alternative in clinical therapy of PCA.
Int J Oncol . 2003 Sep;23(3):721-7
Cancer chemoprevention by resveratrol: in vitro and in vivo
studies and the underlying mechanisms (review).
Cancer, next only to heart diseases, is the second leading cause of deaths
in the United States of America and many other nations in the world. The prognosis
for a patient with metastatic carcinoma of the lung, colon, breast, or prostate
(four of the most common and lethal forms of cancer, which together account
for more than half of all deaths from cancer in the USA ), remains dismal.
Conventional therapeutic and surgical approaches have not been able to control
the incidence of most of the cancer types. Therefore, there is an urgent need
to develop mechanism-based approaches for the management of cancer. Chemoprevention
via non-toxic agents could be one such approach. Many naturally occurring agents
have shown cancer chemopreventive potential in a variety of bioassay systems
and animal models, having relevance to human disease. It is appreciated that
an effective and acceptable chemopreventive agent should have certain properties:
(a), little or no toxic effects in normal and healthy cells; (b), high efficacy
against multiple sites; (c), capability of oral consumption; (d), known mechanism
of action; (e), low cost; and (f), acceptance by human population. Resveratrol
is one such agent. A naturally occurring polyphenolic antioxidant compound
present in grapes, berries, peanuts and red wine. In some bioassay systems
resveratrol has been shown to afford protection against several cancer types.
The mechanisms of resveratrol's broad cancer chemopreventive effects are not
completely understood. In this review, we present the cancer chemopreventive
effects of resveratrol in an organ-specific manner. The mechanisms of the antiproliferative/cancer
chemopreventive effects of resveratrol are also presented. We believe that
continued efforts are needed, especially well-designed pre-clinical studies
in the animal models that closely mimic/represent human disease, to establish
the usefulness of resveratrol as cancer chemopreventive agent. This should
be followed by human clinical trials in appropriate cancer types in suitable
populations.
Int J Oncol . 2003 Jul;23(1):17-28
Glucuronidation of resveratrol, a natural product present
in grape and wine, in the human liver.
1. Resveratrol, a polyphenolic compound present in grape and wine, has beneficial
effects against cancer and protective effects on the cardiovascular system.
It has been shown that the compound is sulphated in human liver and the aims
of the present investigation were to study resveratrol glucuronidation in human
liver microsomes and to determine whether flavonoids inhibit resveratrol glucuronidation.
2. A simple and reproducible radiometric assay for resveratrol glucuronidation
was developed. The assay employed uridine-5'-diphosphoglucuronic acid-[14C]
and unlabelled resveratrol. Resveratrol-glucuronide was isolated by TLC. The
intra- and interassays variabilities were 1 and 1.5%, respectively. 3. The
rate of resveratrol glucuronidation was measured in 10 liver samples. The mean
+/- SD and median of resveratrol glucuronidation rate were 0.69 +/- 0.34 and
0.80 nmol/min/mg, respectively. Resveratrol glucuronosyl transferase followed
Michaelis-Menten kinetics and the Km and Vmax (mean +/- SD; n = 5) were 0.15
+/- 0.09 mM and 1.3 +/- 0.3 nmol/min/mg, respectively. The intrinsic clearance
was 11 +/- 4 x 10(-3) ml/min.mg. 4. The flavonoid quercetin inhibited resveratrol
glucuronidation and its IC50 (mean +/- SD; n = 3) was 10 +/- 1 microM. Myricetin,
catechin, kaempferol, fisetin and apigenin (all at 20 microM) inhibited resveratrol
glucuronidation and the percent of control ranged between 46% (catechin) to
72% (apigenin). 5. The present results show that resveratrol is glucuronated
in the human liver. Glucuronidation may reduce the bioavailability of this
compound however, flavonoids inhibit resveratrol glucuronidation and such an
inhibition might improve the bioavailability of resveratrol.
Xenobiotica. 2000 Nov;30(11):1047-54
Modulating effect of resveratrol and quercetin on oral cancer
cell growth and proliferation.
Resveratrol and quercetin are polyphenols which have been detected in significant
amounts in green vegetables, citrus fruits and red grape wines. Beneficial
effects attributed to these compounds include anti-inflammatory, antiviral
and antitumor properties. The effect of resveratrol and quercetin on growth
of human oral cancer cells is unknown. Resveratrol and quercetin, in concentrations
of 1 to 100 microM, were incubated in triplicates with human oral squamous
carcinoma cells SCC-25 in DMEM-HAM's F-12 supplemented with fetal calf serum
and antibiotics in an atmosphere of 5% CO2 in air at 37 degrees C for 72 h.
Cell growth was determined by counting the number of viable cells with a hemocytometer.
Cell proliferation was measured by means of incorporation of [3H]thymidine
in nuclear DNA. Resveratrol at 10 and 100 microM induced significant dose-dependent
inhibition in cell growth as well as in DNA synthesis. Quercetin exhibited
a biphasic effect, stimulation at 1 and 10 microM, and minimal inhibition at
100 microM in cell growth and DNA synthesis. Combining 50 microM of resveratrol
with 10, 25 and 50 microM of quercetin resulted in a gradual and significant
increase in the inhibitory effect of quercetin on cell growth and DNA synthesis.
We conclude that resveratrol or a combination of resveratrol and quercetin,
in concentrations equivalent to that present in red wines, are effective inhibitors
of oral squamous carcinoma cell (SCC-25) growth and proliferation, and warrant
further investigation as cancer chemopreventive agents.
Anticancer Drugs . 1999 Feb;10(2):187-93
Indole-3-carbinol (I3C) induced cell growth inhibition, G1
cell cycle arrest and apoptosis in prostate cancer cells.
Prostate cancer is one of the most common cancers in men and it is the second
leading cause of cancer related death in men in the United States . Recent
dietary and epidemiological studies have suggested the benefit of dietary intake
of fruits and vegetables in lowering the incidence of prostate cancer. A diet
rich in fruits and vegetables provides phytochemicals, particularly indole-3-carbinol
(I3C), which may be responsible for the prevention of many types of cancer,
including hormone-related cancers such as prostate. Studies to elucidate the
role and the molecular mechanism(s) of action of I3C in prostate cancer, however,
have not been conducted. In the current study, we investigated whether I3C
had any effect against prostate cancer cells and, if so, attempts were made
to identify the potential molecular mechanism(s) by which I3C elicits its biological
effects on prostate cancer cells. Here we report for the first time that I3C
inhibits the growth of PC-3 prostate cancer cells. Induction of G1 cell cycle
arrest was also observed in PC-3 cells treated with I3C, which may be due to
the observed effects of I3C in the up-regulation of p21(WAF1) and p27(Kip1)
CDK inhibitors, followed by their association with cyclin D1 and E and down-regulation
of CDK6 protein kinase levels and activity. The induction of p21(WAF1) appears
to be transcriptionally upregulated and independent of the p53 responsive element.
In addition, I3C inhibited the hyperpohosphorylation of the Retinoblastoma
(Rb) protein in PC-3 cells. Induction of apoptosis was also observed in this
cell line when treated with I3C, as measured by DNA laddering and poly (ADP-ribose)
polymersae (PARP) cleavage. We also found an up-regulation of Bax, and down-regulation
of Bcl-2 in I3C-treated cells. These effects may also be mediated by the down-regulation
of NF-kappaB observed in I3C treated PC-3 cells. From these results, we conclude
that I3C inhibits the growth of PC-3 prostate cancer cells by inducing G1 cell
cycle arrest leading to apoptosis, and regulates the expression of apoptosis-related
genes. These findings suggest that I3C may be an effective chemopreventive
or therapeutic agent against prostate cancer.
Oncogene. 2001 May 24;20(23):2927-36
Grape seed extract inhibits EGF-induced and constitutively
active mitogenic signaling but activates JNK in human prostate carcinoma
DU145 cells: possible role in antiproliferation and apoptosis.
A loss of functional androgen receptor and an enhanced expression of growth
factor receptors and associated ligands are causal genetic events in prostate
cancer (PCA) progression. These genetic alterations lead to an epigenetic mechanism
where a feedback autocrine loop between membrane receptor and ligand (e.g.
EGFR-TGFalpha) results in a constitutive activation of MAPK-Elk1-AP1-mediated
mitogenic signaling in human PCA at an advanced and androgen-independent stage.
We rationalized that inhibiting these epigenetic events could be useful in
controlling advanced PCA growth. Recently, we found that grape seed extract
(GSE), a dietary supplement rich in flavonoid procyanidins, inhibits advanced
and androgen-independent human PCA DU145 cell growth in culture and nude mice.
Here, we performed detailed mechanistic studies to define the effect of GSE
on EGFR-Shc-MAPK-Elk1-AP1-mediated mitogenic signaling in DU145 cells. Pretreatment
of serum-starved cells with GSE resulted in 70% to almost complete inhibition
of EGF-induced EGFR activation and 50% to complete inhibition of Shc activation,
which corroborated with a comparable decrease in EGF-induced Shc binding to
EGFR. Conversely, EGF-induced ERK1/2 phosphorylation was inhibited only by
lower doses of GSE; in fact, higher doses showed an increase. Additional studies
showed that GSE alone causes a dose- and time-dependent increase in ERK1/2
phosphorylation in starved DU145 cells that is inhibited by an MEK1 inhibitor
PD98059. Independent of this increase in ERK1/2 phosphorylation, GSE showed
a strong inhibition of ERK1/2 kinase activity to Elk1 in both cellular and
cell-free systems. GSE treatment of cells also inhibited both EGF-induced and
constitutively active Elk1 phosphorylation and AP1 activation. GSE treatment
also showed DNA synthesis inhibition in starved and EGF-stimulated cells as
well as loss of cell viability and apoptotic death that was further increased
by adding MEK1 inhibitor. Since GSE strongly induced apoptosis independent
of its affect on an increase in phospho-ERK1/2, we hypothesized that apoptotic
effect of GSE could be by other mechanism(s) including its effect on stress-associated
MAPK, the JNK. Indeed, GSE-treated cells showed a strong and sustained increase
in phospho-JNK1/JNK2 levels, JNK activity and phospho-cJun levels. An inhibition
of GSE-induced JNK activation by a novel JNK inhibitor SP600125 resulted in
a significant reversal of GSE-induced apoptotic death suggesting the involvement
of JNK activation by GSE in its apoptosis response. Together, these results
suggest that anticancer effects of GSE in PCA be mediated via impairment of
EGFR-ERK1/2-Elk1-AP1-mediated mitogenic signaling and activation of JNK causing
growth inhibition and apoptosis, respectively.
Oncogene. 2003 Mar 6;22(9):1302-16
Quercetin inhibits the expression
and function of the androgen receptor in LNCaP prostate cancer cells.
The androgen receptor (AR)
is involved in the development and progression of prostate cancer. In
order to find new compounds that may present novel mechanisms to
attenuate the function of AR, we investigated the effect of a natural
flavonoid chemical, quercetin, on androgen action in an androgen-responsive
LNCaP prostate cancer cell line. Western blot analysis showed that AR
protein expression was inhibited by quercetin in a dose-dependent manner.
To demonstrate that the repression effects on AR expression can actually
reduce its function, we found that quercetin inhibited the secretion
of the prostate-specific, androgen-regulated tumor markers, PSA and
hK2. The mRNA levels of androgen-regulated genes such as PSA, NKX3.1
as well as ornithine decarboxylase (ODC) were down-regulated by quercetin.
Transient transfections further showed that quercetin inhibited AR-mediated
PSA expression at the transcription level. Finally, it was demonstrated
that quercetin could repress the expression of the AR gene at the
transcription level. Our result suggests that quercetin can attenuate
the function of AR by repressing its expression and has the potential
to become a chemopreventive and/or chemotherapeutic agent for prostate
cancer.
Carcinogenesis . 2001 Mar;22(3):409-1
Wine antioxidant polyphenols inhibit the proliferation of
human prostate cancer cell lines.
The effect of different wine antioxidant polyphenols (catechin, epicatechin,
quercetin, and resveratrol) on the growth of three prostate cancer cell lines
(LNCaP, PC3, and DU145) was investigated. A dose- and time-dependent inhibition
of cell growth by polyphenols was found at nanomolar concentrations. The proliferation
of LNCaP and PC3 cells was preferentially inhibited by flavonoids (catechin,
epicatechin, and quercetin), whereas resveratrol was the most potent inhibitor
of DU145 cell growth. Possible mechanisms of action were investigated: 1) The
competition of polyphenols for androgen binding in LNCaP cells revealed significant
interaction only in the case of high concentrations of quercetin, at least
at five orders of magnitude higher than the concentrations needed for cell
growth inhibition. All other phenols showed low interactions. 2) Oxygen species
production after mitogen stimulation and H2O2 sensitivity of these cell lines
did not correlate with the observed antiproliferative effects, ruling out such
a mode of action. 3) NO production revealed two different patterns: LNCaP and
DU145 cells produced high concentrations of NO, whereas PC3 cells produced
low concentrations. Phorbol ester stimulation of cells did not reveal any additional
effect in LNCaP and DU145 cells, whereas it enhanced the secretion of NO in
PC3 cells. Polyphenols decreased NO secretion. This effect correlates with
their antiproliferative action and the inhibition of inducible NO synthase.
It is therefore proposed that the antiproliferative effect of polyphenols is
mediated through the modulation of NO production. In conclusion, our data show
a direct inhibitory effect of low concentrations of antioxidant wine phenols
on the proliferation of human prostate cancer cell lines mediated by the production
of NO, further suggesting potential beneficial effects of wine and other phenol-containing
foods or drinks for the control of prostate cancer cell growth.
Nutr Cancer . 2000;37(2):223-33
Resveratrol pretreatment desensitizes AHTO-7 human osteoblasts
to growth stimulation in response to carcinoma cell supernatants.
Resveratrol, a natural phytoestrogen, has been reported to promote
differentiation of murine MC3T3-E1 osteoblasts and to inhibit proliferation
of prostate cancer cell lines. In the present study we tested the
effects of resveratrol on the increased proliferation of human AHTO-7
osteoblastic cell line induced by conditioned media (CM) from a panel
of carcinoma cell lines. This compound was found to modulate AHTO-7
proliferation in a tamoxifen-sensitive mechanism at lower concentrations,
but failed to induce the osteoblast differentiation marker alkaline phosphatase
(ALP) in contrast to vitamin D3. The proliferative response of AHTO-7 cells
to conditioned media from carcinoma cell lines was diminished (30-71.4% inhibition)
upon pretreatment with 0.5 microM resveratrol. Highest inhibition was demonstrated
for pancreas (BxPC3, Panc-1), breast (ZR75-1) and renal (ACHN) carcinoma cell
line supernatants whereas the effect on colon carcinoma (SW620, Colo320DM)
cell CM and prostate cancer (PC3, DU145 and LNCaP) CM was less pronounced.
Direct addition of resveratrol affected only supernatants of cell lines (<25%
inhibition) exhibiting growth stimulatory activity for normal WI-38 lung fibroblasts.
Resveratrol inhibited proliferation of DU145 and LNCaP cells in concentrations
exceeding 5 microM, altered cell cycle distribution of all prostate cancer
cell lines in concentrations as low as 0.5 microM, but did not inhibit the
production of osteoblastic factors by these lines. In conclusion, resveratrol
failed to induce ALP activity as marker of osteoblast differentiation in human
osteoblastic AHTO-7 cells, however, inhibited their response to osteoblastic
carcinoma-derived growth factors in concentrations significantly lower than
those to reduce growth of cancer cells, thus effectively modulating tumor -
osteoblast interaction.
Int J Oncol . 1999 Nov;15(5):955-9
Indole-3-carbinol is a negative regulator of estrogen receptor-alpha
signaling in human tumor cells.
Estrogen, via its binding to the estrogen receptor (ER), plays an important
role in breast cancer cell proliferation and tumor development. Indole-3-carbinol
(I3C), a compound occurring naturally in cruciferous vegetables, exhibits a
potent antitumor activity via its regulation of estrogen activity and metabolism.
This study was designed to determine the effect of I3C on the potential to
inhibit the ER-alpha. Using a reporter gene driven by the estrogen receptor,
I3C (10-125 micromol/L) significantly repressed the 17ss-estradiol (E2)-activated
ER-alpha signaling in a dose-dependent manner. I3C and breast cancer susceptibility
gene 1 (BRCA1) synergistically inhibited transcriptional activity of ER-alpha.
Moreover, I3C down-regulated the expression of the estrogen-responsive genes,
pS2 and cathepsin-D, and up-regulated BRCA1. The inhibitory effects of I3C
did not contribute to its cytotoxic effects because these activities were observed
at less than toxic concentrations. These results further suggest that antitumor
activities of I3C are associated not only with its regulation of estrogen activity
and metabolism, but also its modulation of ER transcription activity.
J Nutr . 2000 Dec;130(12):2927-31
Cytostatic and antiestrogenic effects of 2-(indol-3-ylmethyl)-3,3'-diindolylmethane,
a major in vivo product of dietary indole-3-carbinol.
Under acidic conditions, indole-3-carbinol (13C) is converted to a series of
oligomeric products thought to be responsible for the biological effects of
dietary 13C. Chromatographic separation of the crude acid mixture of 13C, guided
by cell proliferation assay in human MCF-7 cells, resulted in the isolation
of 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr-1) as a major antiproliferative
component. LTr-1 inhibited the growth of both estrogen-dependent (MCF-7) and
-independent (MDA-MB-231) breast cancer cells by approximately 60% at a non-lethal
concentration of 25 microM. LTr-1 had no apparent effect on the proliferation
of MCF-7 cells in the absence of estrogen. LTr-1 was a weak ligand for the
estrogen receptor (ER) (IC50 70 microM) and efficiently inhibited the estradiol
(E2)-induced binding of the ER to its cognate DNA responsive element. The antagonist
effects of LTr-1 also were exhibited in assays of endogenous pS2 gene expression
and in cells transiently transfected with an estrogen-responsive reporter construct
(pERE-vit-CAT). LTr-1 activated both binding of the aryl hydrocarbon (Ah) receptor
to its cognate DNA responsive element and expression of the Ah receptor-responsive
gene CYP1A1. LTr-1 was a competitive inhibitor of CYP1A1-dependent ethoxyresorufin-O-deethylase
(EROD) activity. In summary, these results demonstrated that LTr-1, a major
in vivo product of I3C, could inhibit the proliferation of both estrogen-dependent
and -independent breast tumor cells and that LTr-1 is an antagonist of estrogen
receptor function and a weak agonist of Ah receptor function.
Biochem Pharmacol . 1999 Sep 1;58(5):825-34
Plant-derived 3,3'-Diindolylmethane is a strong androgen antagonist
in human prostate cancer cells.
3,3'-Diindolylmethane (DIM) is a major digestive product of indole-3-carbinol,
a potential anticancer component of cruciferous vegetables. Our results indicate
that DIM exhibits potent antiproliferative and antiandrogenic properties in
androgen-dependent human prostate cancer cells. DIM suppresses cell proliferation
of LNCaP cells and inhibits dihydrotestosterone (DHT) stimulation of DNA synthesis.
These activities were not produced in androgen-independent PC-3 cells. Moreover,
DIM inhibited endogenous PSA transcription and reduced intracellular and secreted
PSA protein levels induced by DHT in LNCaP cells. Also, DIM inhibited, in a
concentration-dependent manner, the DHT-induced expression of a prostate-specific
antigen promoter-regulated reporter gene construct in transiently transfected
LNCaP cells. Similar effects of DIM were observed in PC-3 cells only when these
cells were co-transfected with a wild-type androgen receptor expression plasmid.
Using fluorescence imaging with green fluorescent protein androgen receptor
and Western blot analysis, we demonstrated that DIM inhibited androgen-induced
androgen receptor (AR) translocation into the nucleus. Results of receptor
binding assays indicated further that DIM is a strong competitive inhibitor
of DHT binding to the AR. Results of structural modeling studies showed that
DIM is remarkably similar in conformational geometry and surface charge distribution
to an established synthetic AR antagonist, although the atomic compositions
of the two substances are quite different. Taken together with our published
reports of the estrogen agonist activities of DIM, the present results establish
DIM as a unique bifunctional hormone disrupter. To our knowledge, DIM is the
first example of a pure androgen receptor antagonist from plants.
J Biol Chem . 2003 Jun 6;278(23):21136-45. Epub 2003 Mar 27.
Distinct forms of hepatic androgen 6 beta-hydroxylase induced
in the rat by indole-3-carbinol and pregnenolone carbonitrile.
The ability of indole-3-carbinol (IC), an anticarcinogen present in cruciferous
vegetables, to induce CYP1A1, CYP1A2, CYP2B1/2, CYP2E1 and CYP3A1/2 in female
rat liver was determined by Western analysis using monoclonal antibodies and
compared to effects produced by pregnenolone carbonitrile in animals of both
sexes. The ontogeny of induction of these cytochrome P450 isozymes in response
to oral administration of IC was also investigated. An inverse correlation
was observed between the 6 beta-hydroxylation of androsterone (A) and the induction
by IC of CYP3A1/2, the P450 isozyme responsible for the bulk of hepatic 6 beta-hydroxylation
of 4-androstenedione (AD). The effect of inhibitors on the formation of 6 beta-OHA
from A or AD was also determined and shown to differ from their action on the
P450 isozymes involved in the formation of the 6 beta-hydroxylated derivatives
of AD or lithocholic acid. The results indicate that the enzyme induced by
IC is distinct from the CYP3A1/2 which catalyzes hydroxylations at position
6 beta, allylic in AD but not in the fully saturated ring system of A. The
increased hepatic conversion of A to its biologically less active 6 beta-OHA
metabolite after treatment of female rats with IC could possibly contribute
to the anticarcinogenic action of indole carbinols. It is also proposed that
the action of multiple inducers present in cruciferous and other vegetables
might produce androgen metabolic profiles very different from those produced
by individual components isolated from them.
J Steroid Biochem Mol Biol . 1994 Nov;51(3-4):219-25
Acid reaction products of indole-3-carbinol and their effects
on cytochrome P450 and phase II enzymes in rat and monkey hepatocytes.
The effects of three acid condensation products of indole-3-carbinol
(I3C), i.e. 3,3'-diindolylmethane (DIM), 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b"]tri-indole
(CTI) and 2,3-bis[3-indolylmethyl]indole (BII), on cytochrome P450 and phase
II enzymes were studied in primary cultures of rat and cynomolgus monkey liver
cells. In rat hepatocytes all three indole derivatives dose-relatedly induced
the ethoxyresorufin O-dealkylation (EROD) activity (to 24-fold) and 7 alpha-hydroxylation
of testosterone (to 4-fold), whereas all three decreased the 16 alpha- and
2 alpha-testosterone hydroxylation (DIM to 60%, CTI and BII to a mere 5% of
the control cells). Treatment of monkey hepatocytes with DIM and BII enhanced
the EROD activity to 6- and 9-fold, respectively. Furthermore, BII decreased
the 6 beta-hydroxylation of testosterone (to 60% of the untreated cultures)
in monkey cells. Phase II enzymes were also affected. In rat hepatocytes DIM,
CTI and BII enhanced DT-diaphorase (DTD) (= NAD(P)H-quinone reductase) activity,
and DIM and BII the glucuronidation of 1-naphthol. In monkey cells BII only
enhanced DTD, and no changes were observed in the glucuronidation of 1-naphthol
after treatment with either DIM or BII. The indole derivatives did not affect
glutathione S-transferase activity and sulfation of 1-naphthol in either rat
or monkey hepatocytes. These results identify two novel acid condensation products
of I3C, CTI and BII, as potent compounds in affecting biotransformation in
rat as well as in monkey hepatocytes.
Biochem Pharmacol . 1992 Apr 1;43(7):1439-47
Resveratrol, a natural product derived from grape, exhibits
antiestrogenic activity and inhibits the growth of human breast cancer
cells.
Resveratrol is a natural phytoalexin compound found in grapes and other food
products. In this study, the effect of resveratrol on the growth of human breast
cancer cells was examined. Results show that resveratrol inhibits the growth
of estrogen receptor(ER)-positive MCF-7 cells in a dose-dependent fashion.
Detailed studies with MCF-7 cells demonstrate that resveratrol antagonized
the growth-promoting effect of 17-beta-estradiol (E2) in a dose-dependent fashion
at both the cellular (cell growth) and the molecular (gene activation) levels.
At 5 x 10(-6) M, resveratrol abolished the growth-stimulatory effect mediated
by concentrations of E2 up to 10(-9) M. The antiestrogenic effect of resveratrol
could be observed at a concentration of 10(-6) M and above. The antiestrogenic
effect of resveratrol was also demonstrated at the molecular level. Resveratrol
in a dose-dependent fashion antagonized the stimulation by E2 of progesterone
receptor gene expression in MCF-7 cells. Moreover, expression of transforming
growth factor-alpha and insulin-like growth factor I receptor mRNA was inhibited
while the expression of transforming growth factor beta2 mRNA was significantly
elevated in MCF-7 cells cultivated in the presence of resveratrol (10(-5) M).
In summary, our results show that resveratrol, a partial ER agonist itself,
acts as an ER antagonist in the presence of estrogen leading to inhibition
of human breast cancer cells.
J Cell Physiol . 1999 Jun;179(3):297-304 |