Synergistic growth inhibition of prostate cancer cells by 1 alpha,25 Dihydroxyvitamin D-3 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 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 cor relate clearly with the antiproliferative effects of 1 alpha ,25(OH)(2)D-3 and therefore it is unclear why prostate cancer cell lines are significantl y 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 tr ichostatin A (TSA) are inhibitors of histone deacetylase (HDAC) activity. L ow doses of NaB or TSA (300 muM and 15 nM respectively), which alone were r elatively inactive, synergized with 1 alpha ,25(OH)(2)D-3 in liquid and sem i-solid agar to inhibit the growth of LNCaP, PC-3 and DU-145 prostate cance r cells. Still greater synergy was observed between vitamin D-3 hexafluorid e analogs and either NaB or TSA, The mechanism appeared to involve neither the cyclin-dependent kinase inhibitor, p21((waf1/cip1)) nor cell cycle arre st, but rather induction of apoptosis, These data suggest that cells dysreg ulate the normal pro-apoptotic signals of 1 alpha ,25(OH)(2)D-3 during pros tate cancer development by a mechanism involving histone deacetylation, Com bination therapy with potent vitamin D-3 analogs and clinically approved HD AC inhibitors may overcome this lesion and improve the treatment of both an drogen-dependent and independent prostate cancer.