Biscoclaurine alkaloid cepharanthine inhibits the growth of primary effusion lymphoma in vitro and in vivo and induces apoptosis via suppression of the NF-κB pathway

Primary effusion lymphoma (PEL) is a unique and recently identified non-Hodgkin's lymphoma that was originally identified in patients with AIDS. PEL is caused by the Kaposi sarcoma-associated herpes virus (KSHV/HHV-8) and shows a peculiar presentation involving liquid growth in the serous body cavity and a poor prognosis. As the nuclear factor (NF)-kappa B pathway is activated in PEL and plays a central role in oncogenesis, we examined the effect of a biscoclaurine alkaloid, cepharanthine (CEP) on PEL derived cell lines (BCBL-1, TY-1 and RM-P1), in vitro and in vivo. An methylthioletrazole assay revealed that the cell proliferation of PEL cell lines was significantly suppressed by the addition of CEP (1-10 mu g/ml). CEP also inhibited NF-kappa B activation and induced apoptotic cell death in PEL cell lines. We established a PEL animal model by intraperitoneal injection of BCBL-1, which led to the development of ascites and diffuse infiltration of organs, without obvious solid lymphoma formation, which resembles the diffuse nature of human PEL. Intraperitoneal administration of CEP inhibited ascites formation and diffuse infiltration of BCBL-1 without significant systemic toxicity in this model. These results indicate that NF-kappa B could be an ideal molecular target for treating PEL and that CEP is quite useful as a unique therapeutic agent for PEL. (C) 2009 UICC