Cancer Chemoprevention Drug Development Strategies for Resveratrol

Steele, Vernon E.; Wargovich, Michael J.; McKee, Kathy; Sharma, Sheela; Wilkinson, Betty P.; Wyatt, Gail P.; Gao, Pu; Kelloff, Gary J.

doi:10.1076/phbi.36.6.62.4552

Cited by 16 publications

(15 citation statements)

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“…In mammary tumors, the protective effects are seen for both estrogen-dependent and -independent tumors. Dietary genistein also reduces the incidence of aberrant crypts and colon cancer in carcinogen-dosed rats (16). In addition to its cancer preventive effects, genistein has a role in cancer therapy (17,18).…”

Section: Introductionmentioning

confidence: 99%

Genistein, a Dietary Isoflavone, Down-Regulates the MDM2 Oncogene at Both Transcriptional and Posttranslational Levels

et al. 2005

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Although genistein has chemopreventive effects in several human malignancies, including cancers of the breast, colon, and prostate, the mechanisms of action are not fully understood. Herein we report novel mechanisms whereby genistein down-regulates the MDM2 oncogene, perhaps explaining some of its anticancer activities. In a dose-and time-dependent manner, genistein reduced MDM2 protein and mRNA levels in human cell lines of breast, colon, and prostate cancer; primary fibroblasts; and breast epithelial cells. The inhibitory effects were found at both transcriptional and posttranslational levels and were independent of tyrosine kinase pathways. We found that the NFAT transcription site in the region between À132 and +33 in the MDM2 P2 promoter was responsive to genistein. At the posttranslational level, genistein induced ubiquitination of MDM2, which led to its degradation. Additionally, genistein induced apoptosis and G 2 arrest and inhibited proliferation in a variety of human cancer cell lines, regardless of p53 status. We further showed that MDM2 overexpression abrogated genistein-induced apoptosis in vitro and that genistein inhibited MDM2 expression and tumor growth in PC3 xenografts. In conclusion, genistein directly down-regulates the MDM2 oncogene, representing a novel mechanism of its action that may have implications for its chemopreventive and chemotherapeutic effects. (Cancer Res 2005; 65(18): 8200-8)

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Section: Introductionmentioning

confidence: 99%

Genistein, a Dietary Isoflavone, Down-Regulates the MDM2 Oncogene at Both Transcriptional and Posttranslational Levels

et al. 2005

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“…Purified genistein inhibited the growth of a wide range of cultured cancer cells like leukaemia, breast and prostate cancer, and lymphoma Kondo et al, 1991;Watanabe et al, 1991;Barnes, 1991, 1993;Pagliacci et al, 1993;Buckley et al, 1993). In vivo studies also demonstrated that genistein reduced both the incidence and the multiplicity of DMBA-induced mammary tumours and azoxymethane-induced colon tumours in rats (Lamartiniere et al, 1994;Steele et al, 1995). Among other enzymes, genistein inhibits the activity of protein tyrosine kinase (PTK) and topoisomerase II (Akiyama et al, 1987;Markovits et al, 1989).…”

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confidence: 99%

Inhibition of growth and induction of differentiation of metastatic melanoma cells in vitro by genistein: chemosensitivity is regulated by cellular p53

Rauth

Kichina²,

Green³

1997

Br J Cancer

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Summary We have investigated the effect of the soybean isoflavone genistein on the growth and differentiation of human melanoma cells. Four human melanoma cell lines, either completely lacking or containing different levels of wild-type p53, were treated with genistein in vitro in culture. It has been found that genistein significantly inhibited cell growth and that the chemosensitivity might depend on cellular p53 content. Specifically, the data suggest that high levels of wild-type p53 expression make cells resistant to genistein's growth-inhibitory action. Further support for this observation came from the stable transfection studies in which p53 transfectants expressing high levels of wild-type p53 became resistant to genistein. With respect to cell differentiation, our study showed that genistein increased melanin content and tyrosinase activity and caused the cells to form dendrite-like structures. Cells lacking p53 responded more than cells with p53 to dendrite-like structure formation. We also observed that genistein-induced differentiation involved an increase in tyrosinase mRNA level; the mechanisms by which genistein increases tyrosinase transcripts remain to be elucidated. Genistein treatment of the melanoma cell lines resulted in cell cycle arrest at G2/M check point and no significant apoptosis was observed.

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“…51 ± 53 (2) Genistein possesses antimetastatic activity in prostate, is also growth inhibitory, and is currently undergoing phase I testing as a potential prostate chemopreventive agent. 13,18,54 (3) Tamoxifen, at high concentrations (ie, micromolar range), inhibits protein kinase C (PKC), activating prostate TGFb signaling pathways and leading to growth inhibition, and when given to humans in the form of high dose tamoxifen therapy, is associated with clinical activity in advanced prostate cancer. 17,55 Toremifene and 4-hydroxy tamoxifen, are chemically related to tamoxifen.…”

Section: Discussionmentioning

confidence: 99%

“…However, both classes of agents exhibit prostate speci®c activity and both are being developed as potential prostate chemopreventive agents based upon this activity. 18,51,54 Note, that even though the drug administered to humans is perillyl alcohol, its active metabolite is perillic acid; perillyl alcohol methylester is chemically related to perillyl alcohol.…”

Section: Discussionmentioning

confidence: 99%

Prostate cancer chemoprevention agents exhibit selective activity against early stage prostate cancer cells

Kyle

Patel

et al. 2001

Prostate Cancer Prostatic Dis

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Preclinical models for the identi®cation of prostate cancer chemoprevention agents are lacking. Based upon the notion that clinically useful chemoprevention agents should exhibit selective activity against early stage disease, studies were undertaken to assess whether chemoprevention agents selectively inhibited the growth of early stage prostate cancer, as compared to late stage cancer. First, a series of cell and molecular studies were performed, which, when taken together, validated the use of a panel of prostate cell lines as a model of the different stages of carcinogenesis. Next, therapeutic responsiveness to ten different cytotoxic or chemoprevention agents was evaluated. Chemoprevention agents exhibited selective activity against normal and early transformed prostate tissue, whereas cytotoxic agents were non-speci®c. Selective activity against early versus advanced prostate cancer cells is identi®ed as a potential screening method for chemoprevention agents. Prostate Cancer and Prostatic Diseases (2001) 4, 81±91.

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Cancer Chemoprevention Drug Development Strategies for Resveratrol

Cited by 16 publications

References 0 publications

Genistein, a Dietary Isoflavone, Down-Regulates the MDM2 Oncogene at Both Transcriptional and Posttranslational Levels

Genistein, a Dietary Isoflavone, Down-Regulates the MDM2 Oncogene at Both Transcriptional and Posttranslational Levels

Inhibition of growth and induction of differentiation of metastatic melanoma cells in vitro by genistein: chemosensitivity is regulated by cellular p53

Prostate cancer chemoprevention agents exhibit selective activity against early stage prostate cancer cells

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