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Phenoxodiol inhibits growth of metastatic prostate cancer cells

Authors

  • Martin F. Aguero,

    1. Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington 20057, District of Columbia
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  • Marina Venero,

    1. Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington 20057, District of Columbia
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  • David M. Brown,

    1. Marshall Edwards Inc., 140 Wicks Road, North Ryde 2113, New South Wales, Australia
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  • Mark E. Smulson,

    1. Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington 20057, District of Columbia
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  • Luis A. Espinoza

    Corresponding author
    1. Department of Biochemistry and Molecular and Cellular Biology, Georgetown University Medical Center, Washington 20057, District of Columbia
    • Department of Biochemistry and Molecular and Cell Biology, Georgetown University Medical Center, Basic Science Building, Room 348, 3900 Reservoir Road NW, Washington, DC 20057.
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Abstract

BACKGROUND

Phenoxodiol, a synthetic analog of Genistein, is being assessed in several clinical studies against a range of cancer types and was shown to have a good efficacy and safety profile. In this study we tested the effects of Phenoxodiol against prostate cancer cell lines.

METHODS

Cell-cycle analysis, plasmatic membrane damage, clonogenic assay, comet assay, and Western blot methodologies were employed to assess the effects of Phenoxodiol on prostate cancer cell lines. An in vivo model confirmed the potential therapeutic efficacy of Phenoxodiol when administered orally to tumor bearing mice.

RESULTS

Phenoxodiol treatment promoted a marked inhibition of proliferation and loss of colony formation in LNCaP cells in a dose- and time-dependent manner. Similar effects were also observed in the metastatic prostate cell lines PC3 and DU145. Activation of poly(ADP ribose) polymerase 1 (PARP-1) clearly indicates the induction of DNA damage by Phenoxodiol. Oral administration of Phenoxodiol induced a considerable growth inhibition of malignant tumors generated by inoculation of LNCaP cells into Balb/c nu/nu athymic mice.

CONCLUSIONS

These data demonstrated that Phenoxodiol promotes apoptosis, as determined by PARP-1 degradation, via mitochondrial depolarization and G1/S cell-cycle arrest thereby confirming that it is active against androgen-dependent and independent prostate cancer cells. Although a precise target for Phenoxodiol has not been identified, these data contribute to our understanding of the mechanism by which this drug promotes cell death in prostate cancer cells, and warrants the continued clinical development of Phenoxodiol as a therapeutic for the treatment of metastatic prostate cancer. Prostate 70: 1211–1221, 2010. © 2010 Wiley-Liss, Inc.

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