Effects of the flavonoid drug quercetin on the
response of human prostate tumours to hyperthermia in vitro and in vivo.
Asea A, Ara G, Teicher BA, Stevenson MA, Calderwood SK.
Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard
Medical School, Boston, MA 02115, USA.
Tumour hyperthermia, although potentially a powerful therapeutic agent and
radiation sensitizer, is hindered by a number of considerations including
inhomogeneous heating of deep seated tumours due to energy deposition and
perfusion issues. One solution is to design hyperthermia sensitizers to
amplify the effects of hyperthermia, particularly at cold spots within the
tumour undergoing treatment. This study examined the use of Quercetin,
a flavonoid drug shown previously to antagonize the expression of
HSP72 and induce apoptosis as a sensitizer of prostate cancer growth in
vivo. Quercetin
dose-dependently suppressed PC-3 tumour growth in vitro and in vivo. When
combined in a treatment protocol with hyperthermia, quercetin
drastically inhibited tumour growth and
potently amplified the effects
of hyperthermia on two prostate
tumour types, PC-3 and DU-145 in vivo. These experiments, thus,
suggest the use of Quercetin as a hyperthermia sensitizer in the
treatment of prostate carcinoma.
PMID: 11471985 [PubMed - indexed for MEDLINE]
Clin Diagn
Lab Immunol. 2004 Jan;11(1):63-9
Inhibition of prostate cancer cell colony formation by the flavonoid
quercetin correlates with modulation of specific regulatory genes.
Division of Allergy, Immunology and Rheumatology, Department of Medicine,
State University of New York at Buffalo and Kaleida Health, Buffalo, New
York 14203, USA.
The natural product quercetin is a flavonoid found in many fruits and
vegetables. Previous research has shown that
quercetin has antitumor,
anti-inflammatory, antiallergic, and antiviral activities. In the present
investigation we studied the effect of quercetin on the ability of
prostate
cancer cell lines with various degrees of aggressive potential to form
colonies in vitro. Specifically, we examined the molecular mechanisms
underlying this effect, including the expression of cell cycle and tumor
suppressor genes as well as oncogenes. We observed that
quercetin at
concentrations of 25 and 50 micro M significantly inhibited the growth of
the highly aggressive PC-3 prostate cancer cell line and the moderately
aggressive DU-145 prostate cancer cell line, whereas it did not affect
colony formation by the poorly aggressive LNCaP
prostate cancer cell line or
the normal fibroblast cell line BG-9. Using the gene array methodology, we
found that quercetin significantly inhibited the expression of specific oncogenes and genes controlling G(1), S, G(2), and M phases of the cell
cycle. Moreover, quercetin reciprocally up-regulated the expression of
several tumor suppressor genes. In conclusion, our results demonstrate that
the antitumor effects of quercetin directly correlate with the aggressive
potential of prostate cancer cells and that the mechanism(s) of
quercetin-mediated antitumor effects may involve up-regulation of tumor
suppressor genes and reciprocal down-regulation of oncogenes and cell cycle
genes. The results of these studies provide a scientific basis for the
potential use of flavonoids as nutraceuticals in the chemoprevention of
cancer.
PMID: 14715546 [PubMed - indexed for MEDLINE]
Int J Oncol. 2003
Sep;23(3):821-9.
Inhibition of ErbB-2 and ErbB-3 expression by
quercetin prevents transforming growth factor alpha (TGF-alpha)- and
epidermal growth factor (EGF)-induced human PC-3 prostate cancer cell
proliferation.
Huynh H, Nguyen TT, Chan E, Tran E.
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular
Research, National Cancer Centre of Singapore, Singapore 169610, Republic of
Singapore. cmrhth@nccs.com.sg
Because ErbB-2 receptor is involved in hormone-independency for growth and
metastasis of prostate cancer
cells, the aim was to investigate the effects of quercetin on ErbB-2
and ErbB-3 expression and its critical components such as MAP kinase and
PI-3 kinase. Hemocytometric counts and [3H]-thymidine incorporation were
used to determine the effects of quercetin, EGF and TGF-alpha on cell
proliferation and DNA synthesis in PC-3 and LnCap cells. Changes in ErbB-2,
ErbB-3 and components of MAPK and PI-3K pathways were analyzed by Western
blot analysis. Treatment of PC-3 and
LnCap cells with quercetin resulted in a dose-dependent growth
inhibition. The rate of DNA synthesis was decreased by 40, 55 and 65%
on treatment with 14.5, 29.0 and 58.0 microM of quercetin,
respectively. Concomitantly, these treatments led to a dose-dependent
decrease in ErbB-2, ErbB-3 and their basal autophosphorylation levels as
compared to controls. Cyclin D1 expression and basal phosphorylation of c-Raf,
MAPK, Elk-1 and Akt-1 in PC-3 cells was also inhibited by quercetin
treatment. Co-treating PC-3 cells with quercetin significantly
attenuated EGF- and TGF-alpha-induced growth and phosphorylation of ErbB-2,
ErbB-3, c-Raf, MAPK kinase 1/2 (MEK1/2), MAPK, Elk-1 and Akt-1. Since ErbB
receptor is important for growth, metastasis and drug resistance, inhibition
of ErbB-2 and ErbB-3 by
pharmacological doses of quercetin may provide a new approach for
treatment of prostate cancers.
PMID: 12888923 [PubMed - indexed for MEDLINE]
Carcinogenesis,
Vol. 22, No. 3, 409-414, March 2001
Quercetin inhibits the expression and function of the
androgen receptor in LNCaP prostate cancer cells
Nianzeng Xing,
Yi Chen, Susan H. Mitchell and Charles Y.F.
Young,1
Department of Urology and Biochemistry and Molecular
Biology, Mayo Graduate School, Mayo Foundation, Rochester, MN 55905, USA
The androgen receptor (AR) is involved in the
development andprogression of prostate cancer. In order to find
new compoundsthat may present novel mechanisms to attenuate the
functionof AR, we investigated the effect of a natural
flavonoid chemical,quercetin, on androgen action in an
androgen-responsive LNCaPprostate cancer cell line. Western blot
analysis showed thatAR protein expression was inhibited by
quercetin in a dose-dependentmanner. To demonstrate that the
repression effects on AR expressioncan actually reduce its
function, we found that quercetin inhibitedthe secretion of the
prostate-specific, androgen-regulated tumormarkers, PSA and hK2.
The mRNA levels of androgen-regulatedgenes such as PSA,
NKX3.1 as well as ornithine decarboxylase(ODC)
were down-regulated by quercetin. Transient transfectionsfurther
showed that quercetin inhibited AR-mediated PSA expressionat the
transcription level. Finally, it was demonstrated thatquercetin
could repress the expression of the AR gene at thetranscription
level. Our result suggests that quercetin canattenuate the
function of AR by repressing its expression andhas the potential
to become a chemopreventive and/or
chemotherapeuticagent for prostate cancer.
Excerpts: "Quercetin
is an abundant, naturally occurring flavonoid compound
that can be found in apples, onions, tea, and red wine.It has been reported that this compound shows growth inhibitoryeffects on many different cancer cell lines in vitro and invivo.
"In summary, the
natural polyphenolicquercetin can inhibit theAR
expression at the transcriptional level, and thereby down-regulatethe androgen-inducible genes including PSA, hK2,
NKX3.1 andODC, which play roles in development and
progression of prostatecancer.
Quercetin has the potential to
become a chemopreventiveand/or chemotherapeutic agent for
prostate cancer."
Urology. 1999 Dec;54(6):960-3.
Quercetin in men with category III chronic prostatitis: a preliminary
prospective, double-blind, placebo-controlled trial.
Shoskes DA, Zeitlin SI, Shahed A, Rajfer J.
Institute for Male Urology, Encino,
California, USA.
OBJECTIVES: The National Institutes of Health (NIH) category III chronic
prostatitis syndromes (nonbacterial chronic prostatitis and prostatodynia)
are common disorders with few effective therapies.
Bioflavonoids have recently
been shown in an open-label study to improve the symptoms of these disorders
in a significant proportion of men. The aim of this study was to
confirm these findings in a prospective randomized, double-blind,
placebo-controlled trial. METHODS: Thirty men with category IIIa and IIIb
chronic pelvic pain syndrome were randomized in a double-blind fashion to
receive either placebo or the bioflavonoid quercetin 500 mg twice
daily for 1 month. The NIH chronic prostatitis symptom score was used to
grade symptoms and the quality-of-life impact at the start and conclusion of
the study. In a follow-up unblind, open-label study, 17 additional men
received 1 month of a supplement containing quercetin, as well as bromelain
and papain (Prosta-O), which enhance bioflavonoid absorption.
RESULTS: Two patients in the placebo group refused to complete the study
because of worsening symptoms, leaving 13 placebo and 15 bioflavonoid
patients for evaluation in the blind study. Both the quercetin and placebo
groups were similar in age, symptom duration, and initial symptom score.
Patients taking placebo had a mean improvement in NIH symptom score from
20.2 to 18.8 (not significant), while
those taking the bioflavonoid
had a mean improvement from 21.0 to 13.1 (P = 0.003). Twenty percent
of patients taking placebo and 67%
of patients taking the bioflavonoid had an improvement of symptoms of
at least 25%. In the 17 patients who received Prosta-Q in the
open-label study, 82% had at least a 25% improvement in symptom score.
CONCLUSIONS: Therapy with the
bioflavonoid quercetin is well tolerated and
provides significant symptomatic
improvement in most men with chronic pelvic pain syndrome.
Inhibition of proteasome activity by various fruits and vegetables is
associated with cancer cell death.
Chen
MS, Chen D, Dou QP.
The Prevention Program, Barbara Ann Karmanos Cancer Institute and Department
of Pathology, Wayne State University, School of Medicine, Detroit, Michigan
48201, USA.
There is a large amount of scientific evidence showing that fruits and
vegetables lower the risk of cancer.
However, the responsible molecular mechanisms remain poorly understood. Our
previous studies have demonstrated that inhibition of proteasomal
chymotrypsin-like activity is associated with cancer cell apoptosis, which
may also be the major mechanism responsible for the anticancer effects of
green tea polyphenols. In the current study, we tested the hypothesis
that some fruits and vegetables inhibit tumor cell proteasome activity and
that this inhibition contributes to their cancer-preventative activities. We
report that the extracts of apple
and grape are more potent
than onion, tomato and celery in: (i) inhibiting the proteasomal
chymotrypsin-like activity in leukemia Jurkat T cell extract; (ii)
accumulating the polyubiquitinated proteins in intact Jurkat T cells; (iii)
inducing activation of caspase-3/-7 and cleavage of poly(ADP-ribose)
polymerase in intact Jurkat T cells; and (iv) inducing the appearance of
spherical cells preferentially in
prostate cancer PC-3 over the normal NIH 3T3 cell line. We also found
that strawberry extract had some effect on Jurkat T cell extract and the
prostate PC-3 cell line but
not on intact Jurkat T cells. Our findings suggest that the proteasome is a
cancer-related molecular target for, at least, the
extracts of apple,
grape and onion, and that the inhibition of proteasome activity by these
fruits or vegetable may contribute to their
cancer-preventative effects,
although other molecular mechanisms may also be involved.
PMID: 15011755 [PubMed - indexed for MEDLINE]
Nutr Cancer.
2000;38(1):116-22.
Flavonoids suppress androgen-independent human
prostate tumor proliferation.
Knowles LM, Zigrossi DA, Tauber RA, Hightower C, Milner
JA.
Graduate Program in Nutrition, Nutrition Department, Pennsylvania State
University, University Park, PA 16802, USA.
The present studies compared the effects of selected bioflavonoids on
the proliferation of androgen-independent
human prostatic tumor cells
(PC-3). Complete growth retardation
was observed in PC-3 cells treated with 100 microM quercetin,
kaempferol, and luteolin, while isomolar genistein, apigenin, and myricetin
suppressed PC-3 proliferation by 73%, 70%, and 59%, respectively (p < 0.05).
Naringenin and rutin were not as effective and inhibited growth by < 25%.
Exposure to increasing concentrations of quercetin and kaempferol led
to a dose-dependent decrease in proliferation. Refeeding kaempferol-treated
cells (50 microM) complete medium without the flavonoid resulted in a
return toward control growth rates.
Similar growth recovery was not observed in quercetin-treated cells.
The antiproliferative response of PC-3 cells to quercetin and
kaempferol was additive when supplemented to the medium at 25 microM. A
block in G2-to-M phase progression was observed after the addition of 25
microM kaempferol. When quercetin reached 100 microM, an increase in
the proportion of cells in the S phase became apparent within 24 hours.
Apoptosis was not evident, even when concentrations of quercetin or
kaempferol were raised to 100 microM. The present studies suggest that
alterations in cell cycle progression contribute significantly to the
antiproliferative effects of
quercetin and kaempferol in
PC-3 cells.
PMID: 11341036 [PubMed - indexed for MEDLINE]
Nutr Cancer
2004, Vol. 50, No. 1, Pages 1-7
Review:
Dietary Flavonoids and Cancer Risk: Evidence From Human Population Studies
Marian L. Neuhouser,
Abstract: High dietary intake of fruits
and vegetables is consistently associated with a
reduced risk of common human cancers,
including cancers of the lung, breast,
prostate, and colon. It is
unknown which bioactive compound or compounds in plant foods provide the
chemoprotective effects. One class of compounds currently under
investigation is flavonoids,
a large group of compounds with similar structure, consisting of two
phenolic
benzene rings linked to a heterocyclic pyran or pyrone. Although there are
numerous in vitro and animal model data suggesting that
flavonoids influence
important cellular and molecular mechanisms related to carcinogenesis,
such as cell cycle control and apoptosis, there are limited data from human
population studies. This article reviews data from four cohort studies and
six case-control studies, which have examined associations of flavonoid
intake with cancer risk. There is
consistent evidence from these studies that flavonoids, especially
quercetin, may reduce the risk of lung cancer. Further research
using new dietary databases for food flavonoid content is needed to
confirm these findings before specific public health recommendations about
flavonoids can be formulated.
J Biol Chem. 2004 Nov 8
Induction of cancer cell apoptosis by flavonoids is
associated with their ability to inhibit fatty acid synthase activity.
Brusselmans K, Vrolix R, Verhoeven G, Swinnen JV.
LEGENDO, K.U.Leuven, Leuven B-3000.
The consumption of food products containing high amounts of flavonoids has
been reported to lower the risk of various cancers. The mechanisms
underlying the cancer-protective effects of these naturally occurring
polyphenolic compounds, however, remain elusive. Based on our previous
finding that the cytotoxic effect of the flavanol epigallocatechin-3-gallate
(EGCG) on prostate cancer cells correlates with its ability to inhibit fatty
acid synthase (FAS, a key lipogenic enzyme overexpressed in many human
cancers), we examined the anti-lipogenic effects of a panel of 18 naturally
occurring polyphenolic compounds. In addition to EGCG, 5 other
flavonoids,
more particularly luteolin, quercetin, kaempferol, apigenin and taxifolin,
also markedly inhibited cancer cell lipogenesis. Interestingly, in both
prostate and breast cancer cells,
a remarkable dose-response parallelism was
observed between flavonoid-induced inhibition of fatty acid synthesis,
inhibition of cell growth and induction of apoptosis. In support for a role
of fatty acid synthesis in these effects, addition of exogenous palmitate,
the end product of FAS, markedly suppressed the cytotoxic effects of
flavonoids. Taken together, these findings indicate that the potential of
flavonoids to induce apoptosis in cancer cells is strongly associated with
their FAS inhibitory properties, thereby providing a new mechanism by which
polyphenolic compounds may exert their cancer-preventive and antineoplastic
effects.
Excerpts:
"Consumption of onions and/or
apples, two major
sources of the flavonol quercetin
was inversely associated with the incidence of cancer of the prostate,
lung, stomach and breast.
"Out of 18 naturally occurring
polyphenolic compounds,
luteolin, quercetin
and kaempferol inhibited lipogenesis
by more than 50%. Luteolin,
quercetin
and kaempferol induce growth arrest
of prostate and breast cancer cells. Luteolin,
quercetin and
kaempferol induce apoptosis in
prostate and breast cancer cells.
"Importantly, a
striking correlation was observed between the lipogenesis inhibitory effect
of the polyphenolic compounds and their cytotoxic effect on cancer
cells.
"The potential contribution of flavonoids to the
cancer-preventive effects of
polyphenol-rich diets of course depends on the daily intake and
uptake of these compounds. The average flavonoid intake in the
western world has been estimated at 1000 to 1100 mg per day. However, it is
obvious that significantly larger
flavonoid portions can be taken up by individuals upon frequent
consumption of particular flavonoid rich food products.
"In addition, the
half-life of quercetin in humans is 20-30h, suggesting that
frequent consumption may result in
accumulation of flavonoids in plasma and tissues as previously
observed for green tea
polyphenols.
"Importantly, our data demonstrate that luteolin,
quercetin and kaempferol already
inhibit FAS activity in cancer cells at relatively low concentrations...
which also induce significant cancer
cell death. It should be mentioned that flavonoids may also
contribute to cancer prevention by other mechanisms such as radical
scavenging, detoxification of mutagenic xenobiotics, and inhibition of
topoisomerases, cyclindependent kinases and protein kinases (including
phosphatidyl inositol 3kinase).
"Taken together, our
findings show that flavonoids constitute interesting candidate
molecules for cancer-preventive and/or antineoplastic therapies..."
PMID: 15533929 [PubMed - as supplied by publisher]
Nutr Cancer.
2004;49(2):200-8.
Phytoestrogens in common herbs regulate prostate
cancer cell growth in vitro.
Department of Biochemistry and the Missouri University Center for
Phytonutrient and Phytochemical Studies, University of Missouri, Columbia
65211, USA.
Prostate cancer is an
important public health problem in the United States. Seven phytoestrogens
found in common herbal products were screened for estrogen receptor binding
and growth inhibition of androgen-insensitive (PC-3) and androgen-sensitive
(LNCaP) human prostate tumor cells.
In a competitive 3H-estradiol ligand binding assay using mouse uterine
cytosol, 2.5 M quercetin,
baicalein, genistein, epigallocatechin gallate (EGCG), and curcumin
displaced > 85% of estradiol
binding, whereas apigenin and resveratrol displaced > 40%. From growth
inhibition studies in LNCaP cells, apigenin and curcumin were the most
potent inhibitors of cell growth, and EGCG and baicalein were the least
potent. In PC-3 cells, curcumin was the most potent inhibitor of cell
growth, and EGCG was the least potent. In both cell lines,
significant arrest of the cell cycle
in S phase was induced by
resveratrol and EGCG and in G2M phase by
quercetin, baicalein,
apigenin, genistein, and curcumin.
Induction of apoptosis was induced by all of the 7 compounds in the 2
cell lines as shown by TUNEL and DNA fragmentation assays. Androgen
responsiveness of the cell lines did not correlate with cellular response to
the phytoestrogens. In conclusion,
these 7 phytoestrogens, through different mechanisms, are effective
inhibitors of prostate tumor cell growth.
PMID: 15489213 [PubMed - in process]
Cancer Lett. 2004
Sep 30;213(2):155-63
Overexpression of c-Jun induced by quercetin and
resverol inhibits the expression and function of the androgen receptor in
human prostate cancer cells.
Yuan H, Pan Y, Young CY.
Department of Urology, Mayo Clinic college of Medicine, Mayo Clinic,
Guggenheim Building 520B, Rochester, MN 55905, USA.
Previously, we reported that
quercetin and resveratrol inhibit the function of androgen
receptor (AR). Further studies showed that these two
polyphenols caused an
increase in expression of c-Jun as well as its phosphorylated form in a
dose-dependent manner in prostatic
cell lines. Gel shift assay showed that induced c-Jun has specific
DNA binding activity. Transient transfections demonstrated that c-Jun
repressed prostate-specific antigen promoter activity and transcriptional
activity of the AR promoter. These results support a mechanism in which
overexpressed c-Jun mediates inhibitory effect on the function of AR.
These polyphenols might
potentially be useful in prostate cancer prevention.
PMID: 15327830 [PubMed - indexed for MEDLINE]
Anticancer Res.
1998 Mar-Apr;18(2A):1117-21.
Bioflavonoids commonly and potently induce tyrosine
dephosphorylation/inactivation of oncogenic proline-directed protein kinase
FA in human prostate carcinoma cells.
Lee SC, Kuan CY, Yang CC, Yang SD.
Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan,
R.O.C.
In this study, we investigate the effect of bioflavonoids on the
activity and phosphotyrosine content of oncogenic proline-directed protein
kinase FA (PDPK FA) in human
prostate carcinoma cells.
Chronic treatment of human prostate carcinoma cells with low concentrations
of quercetin, apigenin, and kaempferol
commonly and potently induced
tyrosine dephosphorylation and
concurrent inactivated oncogenic PDPK FA in a concentration-dependent
manner. This is demonstrated by a specific assay of this kinase's activity
in the immunoprecipitates from the cell extracts followed by immunoblotting
and phosphotyrosine analysis. The results indicate that bioflavonoids
may function as common tyrosine kinase inhibitors to inhibit PDPK
FA-specific tyrosine kinase and thereby to induce tyrosine dephosphorylation/inactivation
of this oncogenic kinase in human carcinoma cells. Under this condition,
quercetin, apigenin,
and kaempferol can also inhibit cell
growth in a similar concentration-dependent manner. The results
further indicate that inhibition of tyrosine phosphorylation/activation of
this oncogenic PDPK represents a new
mode of action mechanism for bioflavonoids during the
antiproliferation process in human carcinoma cells.
