Cepharanthin enhances adriamycin sensitivity by synergistically accelerating apoptosis for adriamycin-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR.

Kuniaki Katsui, Masahiro Kuroda, Yadi Wang, Megumi Komatsu, Kengo Himei, Mitsuhiro Takemoto, Shiro Akaki, Jun-Ichi Asaumi, Susumu Kanazawa, Yoshio Hiraki

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)47-56
Number of pages10
JournalInternational Journal of Oncology
Volume25
Issue number1
Publication statusPublished - Jul 2004

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Osteosarcoma
Doxorubicin
Apoptosis
Cell Line
isosorbide-5-mononitrate
P-Glycoprotein
cepharanthine
Stephania
Necrosis
Glutathione Peroxidase
Alkaloids
Drug Resistance
Nitric Oxide

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cepharanthin enhances adriamycin sensitivity by synergistically accelerating apoptosis for adriamycin-resistant osteosarcoma cell lines, SaOS2-AR and SaOS2 F-AR. / Katsui, Kuniaki; Kuroda, Masahiro; Wang, Yadi; Komatsu, Megumi; Himei, Kengo; Takemoto, Mitsuhiro; Akaki, Shiro; Asaumi, Jun-Ichi; Kanazawa, Susumu; Hiraki, Yoshio.

In: International Journal of Oncology, Vol. 25, No. 1, 07.2004, p. 47-56.

Research output: Contribution to journalArticle

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