Cepharanthin enhances adriamycin sensitivity by synergistically accelerating apoptosis for adriamycin-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR.
Cepharanthin (CEP) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. CEP is reported to inhibit drug resistance by inhibiting P-glycoprotein, a drug efflux pump, and recently to induce apoptosis. In the present study, we examined the effects of CEP as an inhibitor of adriamycin (ADR) resistance on ADR-induced apoptosis and necrosis. First, we established p53-deficient ADR-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR. Resistant cells showed a higher level of intracellular glutathione peroxidase activity than parent cells. P-glycoprotein was overexpressed in resistant cells. The intracellular ADR level of resistant cells was lower than that of parent cells. One micro g/ml CEP eliminated the degradation of intracellular ADR of resistant cells; that is, to a level equivalent to that of the parent cells. CEP of 0.5 micro g/ml, which was not cytotoxic when used alone, significantly increased the ADR sensitivity of resistant cells, to a level similar to the parent cell level. Isosorbide 5-mononitrate, a potential nitric oxide-generation agent, combined with CEP further increased the ADR sensitivity of resistant cells, indicating a synergistic effect of CEP and isosorbide 5-mononitrate on ADR cytotoxicity. Time-lapse microscopic observation revealed that ADR dominantly induced apoptosis much more than necrosis for both parent and resistant cells, and that the use of 0.5 micro g/ml CEP with ADR synergistically accelerated apoptosis in resistant cells. Finally, we clarified the property by which CEP synergistically accelerates ADR-induced apoptosis. This property might be a new mechanism that explains how CEP overcomes ADR resistance.
Katsui
Kuniaki
K
Department of Radiology, Okayama University Medical School, Okayama 700-8558, Japan.
Kuroda
Masahiro
M
Wang
Yadi
Y
Komatsu
Megumi
M
Himei
Kengo
K
Takemoto
Mitsuhiro
M
Akaki
Shiro
S
Asaumi
Jun-Ichi
J
Kanazawa
Susumu
S
Hiraki
Yoshio
Y
D000470:Alkaloids / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D044182:Benzylisoquinolines; D001692:Biological Transport; D001859:Bone Neoplasms; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D012516:Osteosarcoma; D052117:Benzodioxoles
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D004317:Doxorubicin; C006947:cepharanthine; D052117:Benzodioxoles