Biscoclaurine alkaloid cepharanthine inhibits the growth of primary effusion lymphoma in vitro and in vivo and induces apoptosis via suppression of the NF-kappaB 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)-kappaB 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 methylthiotetrazole assay revealed that the cell proliferation of PEL cell lines was significantly suppressed by the addition of CEP (1-10 microg/ml). CEP also inhibited NF-kappaB 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-kappaB could be an ideal molecular target for treating PEL and that CEP is quite useful as a unique therapeutic agent for PEL.
Takahashi-Makise
Naoko
N
Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Honjo, Kumamoto, Japan.
Suzu
Shinya
S
Hiyoshi
Masateru
M
Ohsugi
Takeo
T
Katano
Harutaka
H
Umezawa
Kazuo
K
Okada
Seiji
S
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000627:therapeutic use*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D006566:Herpesviridae Infections / Q000188:drug therapy / Q000473:pathology; D019288:Herpesvirus 8, Human / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D052117:Benzodioxoles
D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D061945:Caspase Inhibitors; D020169:Caspases; D016328:NF-kappa B; C006947:cepharanthine; D052117:Benzodioxoles