Resistance to growth inhibitory and apoptotic effects of phorbol ester andUCN-01 in aggressive cancer cell lines

7-Hydroxystaurosporine (UCN-01), a nonselective inhibitor of protein kinase C (PKC), and phorbol ester (PMA), a PKC activator, are undergoing clinical evaluations. We investigated the effects of UCN-01 and PMA on a panel of p rostate cancer cell lines. While PMA induced p21(WAFI/CPI) and arrest growt h of LNCaP cancer cells (IC50 = 0.5-1 nM), aggressive cancer cell lines (DU 145, PC3, and PC3M) were resistant to PMA (IC50 >5000 nM). Low concentratio ns (25-50 nM) of UCN-01 abrogated PMA-induced p21 and growth arrest in LNCa P cells. These low doses of UCN-01 however did not inhibit proliferation of any prostate cancer cell line. PMA-sensitive LNCaP cells were resistant to clinically relevant concentrations of UCN-01 (IC50 = 1.2 muM), but UCN-01 inhibited growth of DU145 and PC3/3M with an IC50 of 200-400 nM. For compar ison, PMA-sensitive HL60 leukemia cells were sensitive to UCN-01 due to rap id apoptosis caused by UCN-01. In PMA-resistant prostate cancer cells, UCN- 01 downregulated cyclin D1, induced p21, caused morphological differentiati on, and G1-phase arrest leading to slow cell death without caspase activati on. Importantly, normal prostate epithelial cells (PrEC) were very sensitiv e to both PMA (IC50 = 0.2 nM) and UCN-01. In PrEC, UCN-01 downregulated cyc lin D1 and arrest growth with an IC50 less than 100 nM. We conclude that lo ss of sensitivity to either UCN-01 or PMA accompanies progression of prosta te cancer.