RRC ID 42183
Author Katsui K, Kuroda M, Wang Y, Komatsu M, Himei K, Takemoto M, Akaki S, Asaumi J, Kanazawa S, Hiraki Y.
Title Cepharanthin enhances adriamycin sensitivity by synergistically accelerating apoptosis for adriamycin-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR.
Journal Int J Oncol
Abstract 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.
Volume 25(1)
Pages 47-56
Published 2004-7-1
PMID 15201988
MeSH Alkaloids / pharmacology* Antineoplastic Agents, Phytogenic / pharmacology* Apoptosis / drug effects* Benzylisoquinolines Biological Transport Bone Neoplasms Cell Line, Tumor Doxorubicin / pharmacokinetics Doxorubicin / toxicity* Drug Resistance, Neoplasm* Drug Synergism Humans Osteosarcoma
IF 3.899
Times Cited 10
Human and Animal Cells Saos-2(RCB0428)