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Apple Polyphenols and Prostate Health  
Highlights:
 
Effects of the flavonoid drug quercetin on the response of human prostate tumours to hyperthermia in vitro and in vivo, Int J Hyperthermia. 2001
Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes, Clin Diagn Lab Immunol. 2004
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, Int J Oncol. 2003
Quercetin inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells, Carcinogenesis, 2001
Quercetin in men with category III chronic prostatitis: a preliminary prospective, double-blind, placebo-controlled trial, Urology. 1999
Inhibition of proteasome activity by various fruits and vegetables is associated with cancer cell death, In Vivo. 2004
Review: Dietary Flavonoids and Cancer Risk: Evidence From Human Population Studies, Nutr Cancer 2004
Induction of cancer cell apoptosis by flavonoids is associated with their ability to inhibit fatty acid synthase activity, J Biol Chem. 2004
Flavonoids suppress androgen-independent human prostate tumor proliferation, Nutr Cancer. 2000
Phytoestrogens in common herbs regulate prostate cancer cell growth in vitro, Nutr Cancer. 2004
Overexpression of c-Jun induced by quercetin and resverol inhibits the expression and function of the androgen receptor in human prostate cancer cells, Cancer Lett. 2004
Bioflavonoids commonly and potently induce tyrosine dephosphorylation/ inactivation of oncogenic proline-directed protein kinase FA in human prostate carcinoma cells, Anticancer Res. 1998

 

Int J Hyperthermia. 2001 Jul-Aug;17(4):347-56.
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.


Nair HK, Rao KV, Aalinkeel R, Mahajan S, Chawda R, Schwartz SA.

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
2001 Oxford University Press

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Full text of this study is available here

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 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.

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 inhibitory effects on many different cancer cell lines in vitro and in vivo.

"In summary, the natural polyphenolic quercetin can inhibit the AR expression at the transcriptional level, and thereby down-regulate the androgen-inducible genes including PSA, hK2, NKX3.1 and ODC, which play roles in development and progression of prostate cancer. Quercetin has the potential to become a chemopreventive and/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.

Publication Types:
Clinical Trial
Randomized Controlled Trial
PMID: 10604689 [PubMed - indexed for MEDLINE]

 
In Vivo. 2004 Jan-Feb;18(1):73-80.
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.

Shenouda NS, Zhou C, Browning JD, Ansell PJ, Sakla MS, Lubahn DB, Macdonald RS.

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.

PMID: 9615775 [PubMed - indexed for MEDLINE]
 
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