Synergistic effects of danazol and mifepristone on the cytotoxicity of UCN-01 in hormone-responsive breast cancer cells

Background. 7-Hydroxystaurosporine (UCN-01) is a novel antitumor agent as w ell as a potent inhibitor of a variety of protein kinases with a preference to protein kinase C. Because an intimate interaction exists between PKC si gnaling and the ER signaling pathways, sex steroid agonists/antagonists mig ht modulate the cytotoxicity of UCN-01. Materials and Methods. Effects of s ex steroid agonists and antagonists on the UCN-01 cytotoxicity were analyze d by MTT assay in MCF-7/WT and MCF-7/ADR, a multiple drug resistance phenot ype lacking ER and PR. Results. MCF-7/ADR is 23-fold more resistant to UCN- 01 than MCF-7. In MCF-7/WT, danazol and mifepristone enhanced the cytotoxic ity of UCN-01, while these agents did not exert any significant effects on it in MCF-7/ADR. Conclusion. These results suggest that danazol or mifepris tone might enhance the antitumor activity of UCN-01 in hormone-dependent ca ncer cells by interacting with PR.