Cepharanthine inhibits proliferation of cancer cells by inducing apoptosis

Cepharanthine, a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata was examined for a possible apoptosis-inducing effect in murine P388 doxorubicin-sensitive (P388/S) and -resistant (P388/DOX) cells. A significant increase in LDH release from cells was observed after P388/S and P388/DOX cells had been exposed to cepharanthine for 24 h. Cepharanthine (10 micrograms/ml) markedly induced apoptosis in resistant cells after 6 h and 24 h. By the means of agarose electrophoresis the DNA ladder was detected in cell lines treated with cepharanthine for 24 h. Cepharanthine (1-10 micrograms/ml) also induced the production of reactive oxygen species in P388/DOX cells, while no such cepharanthine-induced increase in reactive oxygen species was observed in P388/S cells. Flow cytometry analysis showed a high level of Fas-antigen expression in P388/DOX cells treated with cepharanthine. Furthermore, we found that the inhibitition of DNA and protein synthesis caused by cepharanthine (10 micrograms/ml) was more significant in resistant cells than in sensitive cells. Cepharanthine had no effect on the GSH content of P388/S and P388/DOX cells. Our experimental results suggest that cepharanthin can induce apoptosis both in P388/S and P388/DOX cells, especially in the latter. Apoptosis induced by cepharanthine may be implicated in the production of reactive oxygen species and Fas-antigen expression in tumor cells.