Comparison of the efficacy of 7-hydroxystaurosporine (UCN-01) and other staurosporine analogs to abrogate cisplatin-induced cell cycle arrest in human breast cancer cell lines

DNA-damaging agents such as cisplatin arrest cell cycle progression at eith er the G(1), S, or G(2) phase, although the G(1) arrest is seen only in cel ls expressing the wild-type p53 tumor suppressor protein. Caffeine has been shown to abrogate the S and G(2) arrest in p53-defective cells and to enha nce cytotoxicity, but at concentrations too toxic to administer to humans. We have reported that 7-hydroxystaurosporine (UCN-01) also overcomes S and Gz phase arrest and enhances the cytotoxicity of cisplatin. We show here th at UCN-01 at non-cytotoxic concentrations abrogated S and G(2) arrest induc ed by cisplatin in two p53-defective human breast cancer cell lines. UCN-01 pushed the cells through S phase and mitosis, with subsequent apoptosis. I nhibition of mitosis with nocodazole reduced the apoptosis induced by UCN01 plus cisplatin. Seven staurosporine analogs were compared for their abilit y to abrogate cell cycle arrest. Staurosporine was as effective as UCN-01 a t abrogating S and G(2) arrest, but the concentrations required were cytoto xic. K252a abrogated S phase arrest but failed to abrogate G(2) arrest beca use alone it induced G(2) arrest. Hence, K252a did not enhance cisplatin-in duced cytotoxicity because it failed to push the cells through a lethal mit osis. None of the other analogs influenced cell cycle progression at the co ncentrations tested. Accordingly, UCN-01 was the only analog that overcame cell cycle arrest and enhanced the cytotoxicity of cisplatin while exhibiti ng no cytotoxicity of its own. Hence, UCN01 remains the most promising cand idate for testing clinically in combination with cisplatin. BIOCHEM PHARMAC OL 58;11:1713-1721, 1999. (C) 1999 Elsevier Science Inc.