Cepharanthine activates caspases and induces apoptosis in Jurkat and K562 human leukemia cell lines

Cepharanthine (CEP) is a known membrane stabilizer that has been widely use d in Japan for the treatment of several disorders such as anticancer therap y-provoked leukopenia. We here report that apoptosis was induced by low con centrations (1-5 muM) of CEP in a human leukemia T cell line, Jurkat, and b y slightly higher concentrations (5-10 muM) in a human chronic myelogenous leukemia (CML) cell line K562, which expresses a p210 antiapoptotic Bcr-Abl fusion protein. Induction of apoptosis was confirmed in both Jurkat and K5 62 cells by DNA fragmentation and typical apoptotic nuclear change, which w ere preceded by disruption of mitochondrial membrane potential and were ind uced through a Fas-independent pathway. CEP treatment induced activation of caspase-9 and -3 accompanied by cleavage of PARP, Bid, lamin B-1, and DFF4 5/1CAD in both Jurkat and K562 cells, whereas caspase-8 activation and Akt cleavage were observed only in Jurkat cells. The CEP-induced apoptosis was completely blocked by zVAD-fmk, a broad caspase inhibitor. Interestingly, C EP treatment induced remarkable degradation of the Bcr-Abl protein in K562 cells, and this degradation was prevented partially by zVAD-fmk. When used in combination with a nontoxic concentration of herbimycin A, lower concent rations (2-5 muM) of CEP induced obvious apoptosis in K562 cells with rapid degradation or decrease in the amount of Bcr-Abl and Akt proteins. Our res ults suggest that CEP, which does not have bone marrow toxicity, may posses s therapeutic potential against human leukemias, including CML, which is re sistant to anticancer drugs and radiotherapy. J. Cell. Biochem. 82: 200-214 , 2001. (C) 2001 Wiley-Liss, Inc.