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

Prostate cancer is a major cause of male cancer death. In vitro and in vivo data support a role for 1α,25 Dihydroxyvitamin D (1α,25(OH)D) in regulating the growth and differentiation of the normal prostate gland yet prostate cancer cells appear significantly less sensitive to this action. Vitamin D receptor (VDR) content or mutational status do not correlate clearly with the antiproliferative effects of 1α,25(OH)D 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)D 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)D 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 hexafluoride analogs and either NaB or TSA. The mechanism appeared to involve neither the cyclin-dependent kinase inhibitor, p21 nor cell cycle arrest, but rather induction of apoptosis. These data suggest that cells dysregulate the normal pro-apoptotic signals of 1α,25(OH)D during prostate cancer development by a mechanism involving histone deacetylation. Combination therapy with potent vitamin D analogs and clinically approved HDAC inhibitors may overcome this lesion and improve the treatment of both androgen-dependent and independent prostate cancer.