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Synergistic growth inhibition of prostate cancer cells by 1α,25 Dihydroxyvitamin D3 and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A

Oncogene volume 20, pages 1860–1872 (2001)Cite this article

Abstract

Prostate cancer is a major cause of male cancer death. In vitro and in vivo data support a role for 1α,25 Dihydroxyvitamin D3 (1α,25(OH)2D3) in regulating the growth and differentiation of the normal prostate gland yet prostate cancer cells appear significantly less sensitive to this action. Vitamin D3 receptor (VDR) content or mutational status do not correlate clearly with the antiproliferative effects of 1α,25(OH)2D3 and therefore it is unclear why prostate cancer cell lines are significantly less sensitive to this action. We hypothesized that the antiproliferative responses of prostate cancer cells to 1α,25(OH)2D3 are suppressed by a process involving histone deacetylation. Sodium butyrate (NaB) and trichostatin A (TSA) are inhibitors of histone deacetylase (HDAC) activity. Low doses of NaB or TSA (300 μM and 15 nM respectively), which alone were relatively inactive, synergized with 1α,25(OH)2D3 in liquid and semi-solid agar to inhibit the growth of LNCaP, PC-3 and DU-145 prostate cancer cells. Still greater synergy was observed between vitamin D3 hexafluoride analogs and either NaB or TSA. The mechanism appeared to involve neither the cyclin-dependent kinase inhibitor, p21(waf1/cip1) nor cell cycle arrest, but rather induction of apoptosis. These data suggest that cells dysregulate the normal pro-apoptotic signals of 1α,25(OH)2D3 during prostate cancer development by a mechanism involving histone deacetylation. Combination therapy with potent vitamin D3 analogs and clinically approved HDAC inhibitors may overcome this lesion and improve the treatment of both androgen-dependent and independent prostate cancer.

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Authors and Affiliations

  1. Department of Medicine, Division of Medical Sciences, Birmingham University Medical School, Edgbaston, Birmingham, B15 2TH, UK

    Jasbir S Moore, Elizabeth Walker, Philip M Driver, Jaqueline Engel, Ceri E Edwards & Moray J Campbell

  2. Division of Immunity & Infection, Birmingham University Medical School, Edgbaston, Birmingham, B15 2TH, UK

    Samantha F Rashid & Geoffrey Brown

  3. Hoffman La Roche, Nutley, 07110, New Jersey, NJ, USA

    Milan R Uskokovic

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  1. Samantha F Rashid
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  2. Jasbir S Moore
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†This manuscript was presented in part at the 91st Annual Meeting of the American Association for Cancer Research, San Francisco, April 2000. This manuscript is supported in part by grants from the United Birmingham Hospitals Endowment Fund and Prostate Research Campaign UK

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Rashid, S., Moore, J., Walker, E. et al. Synergistic growth inhibition of prostate cancer cells by 1α,25 Dihydroxyvitamin D3 and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A. Oncogene 20, 1860–1872 (2001). https://doi.org/10.1038/sj.onc.1204269

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  • DOI: https://doi.org/10.1038/sj.onc.1204269

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