Novel 20-epi-vitamin D3 analog combined with 9-cis-retinoic acid markedly inhibits colony growth of prostate cancer cells.

BACKGROUND 1,25 dihydroxyvitamin D3 (1,25D) and retinoids may play an important role in preventing progression of prostate cancer. METHODS We examined the ability of four novel 20-epi-vitamin D3 analogs (CB1093, KH1060, KH1266, and CB1267), either alone or in combination with 9-cis retinoic acid (RA) to inhibit colony growth of a human prostate cancer cell line, LNCaP, using soft agar as well as bone marrow stroma. Also, the effect of these analogs on the cell cycle and expression of Ki-67, p21waf−1, and p27kip1 in LNCaP cells was examined. RESULTS The analog CB1267 was the most potent, with 8 × 10−10 M of the analog inhibiting 50% colony growth (ED50) of LNCaP. 9-cis-RA also inhibited colony growth of LNCaP (ED50, 5 × 10−7 M). Combined, CB1267 and 9-cis-RA synergistically inhibited colony growth and significantly increased the number of LNCaP cells in G0/G1 phase. Cell cycle arrest was associated with increased levels of p21waf−1 and p27kip1 and decreased expression of Ki-67 protein. Pulse-exposure to this combination (5 × 10−8 M) irreversibly inhibited colony growth, both in soft agar and on normal human bone marrow stroma. CONCLUSIONS Combination of a new vitamin D3 analog (CB1267) and a retinoid (9-cis-RA) potently inhibited colony formation of LNCaP prostate cancer cells in vitro, suggesting further studies in animal models. This combination may afford an interesting therapeutic approach to low-burden prostate cancer. Prostate 40:141–149, 1999. © 1999 Wiley-Liss, Inc.