Synergistic growth inhibition of prostate cancer cells by 1α,25 Dihydroxyvitamin D3 and its 19-nor-hexafluoride analgos incombination with either sodium butyrate or trichostatin A
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Prostate cancer is a major cause of male cancer death. In vitro and in vivo data support a role for 1 alpha ,25 Dihydroxyvitamin D-3 (1 alpha ,25(OH)(2)D-3) in regulating the growth and differentiation of the normal prostate gland yet prostate cancer cells appear significantly less sensitive to this action. Vitamin D-3 receptor (VDR) content or mutational status do not correlate clearly with the antiproliferative effects of 1 alpha ,25(OH)(2)D-3 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 1 alpha ,25(OH)(2)D-3 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 muM and 15 nM respectively), which alone were relatively inactive, synergized with 1 alpha ,25(OH)(2)D-3 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 D-3 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 1 alpha ,25(OH)(2)D-3 during prostate cancer development by a mechanism involving histone deacetylation, Combination therapy with potent vitamin D-3 analogs and clinically approved HDAC inhibitors may overcome this lesion and improve the treatment of both androgen-dependent and independent prostate cancer.
|Number of pages||13|
|Publication status||Published - 5 Apr 2001|
- apoptosis, histone deacetylation inhibitors, growth inhibition, prostate cancer, 1 alpha,25 Dihydroxyvitamin D-3