Positive interaction of bisbenzylisoquinoline alkaloid, cepharanthin, with vinca alkaloid agents against human tumors.

Cepharanthin (CE), a bisbenzylisoquinoline alkaloid drug, was tested in vitro and in vivo with chemotherapeutic agents, vincristine (VCR), vinblastine (VLB), and vindesine (VDS). The activity of these agents alone or in combination was tested against a human colon cancer cell line (RPMI 4788) or a human uterine cervical cancer cell line (HeLa), using a modified microcytotoxicity-viable cell staining assay. In the in vitro study, the antiproliferative activities of each vinca alkaloid were enhanced additively or synergistically by combination with CE in RPMI 4788 cells as well as HeLa cells. The sequential exposure of the RPMI 4788 cells or HeLa cells to both CE and each vinca alkaloid agent showed evidence of a more significant potentiation. The antiproliferative activity of the combination of each vinca alkaloid agent(VCR, VLB, or VDS) with CE was almost equivalent to the effect of each vinca alkaloid agent alone which was potentiated by CE tenfold through several hundredfold. In an experimental model of tumor growth and survival, in which RPMI 4788 cells were transplanted subcutaneously or intraperitoneally into BALB/c nu/nu mice respectively, CE (1 mg/kg) alone exerted not significant inhibitory activity against tumor growth or survival, and VCR (0.25 mg/kg) alone partially inhibited these antitumor activities. Furthermore, the antitumor effects of VCR were elevated synergistically by the simultaneous administration of CE. These studies indicate that due to their therapeutic potential, combinations of vinca alkaloid agent with CE might be a promising therapy for some human cancers.