Induction of cell cycle arrest and apoptosis in myeloma cells by cepharanthine, a biscoclaurine alkaloid.
Cepharanthine (CEP), a biscoclaurine alkaloid extracted from Stephania Cepharantha Hayata, has been used in Japan for treating patients with radiation-induced leucopenia or thrombocytopenia. We treated a patient with multiple myeloma (MM), who was not responding to preceding chemotherapy, who coincidently received therapy with CEP due to thrombocytopenia. Since the case showed a marked reduction of tumor load, direct anti-tumor effects of CEP to myeloma cells were investigated in vitro. Anti-tumor effects were observed in all myeloma cell lines tested, including a line resistant to melphalan. Exposure to CEP of a myeloma cell line induced the production of reactive oxygen species, activated the caspase-3 pathway and eventually induced apoptosis. Pre-exposure of cells to a pan-caspase inhibitor, Z-VAD-FMK, or a free radical scavenger, Tiron, effectively blocked CEP-induced apoptosis. Interestingly, CEP also inhibited cell growth of myeloma cells by inducing CDK inhibitors. These data show, for the first time, that CEP has anti-myeloma effects by the activation of apoptotic pathways and blocking cell cycle progression via CDK inhibitors. Although analysis of these two pathways should be clarified further, the use of CEP may be considered as a potential therapeutic agent for a subset of MM.
Kikukawa
Yoshitaka
Y
Department of Hematology, Kumamoto University Hospital, Kumamoto 860-8556, Japan.
Okuno
Yutaka
Y
Tatetsu
Hiro
H
Nakamura
Miki
M
Harada
Naoko
N
Ueno
Shikiko
S
Kamizaki
Yorinori
Y
Mitsuya
Hiroaki
H
Hata
Hiroyuki
H
D000368:Aged; D000470:Alkaloids / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D017382:Reactive Oxygen Species; D052117:Benzodioxoles
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D020169:Caspases; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; C006947:cepharanthine; D052117:Benzodioxoles