Apoptosis induced by doxorubicin and cinchonine in P388 multidrug-resistant cells.
Acquired drug resistance is a major factor in the failure of doxorubicin-based cancer chemotherapy. We determined the ability of cinchonine to reverse doxorubicin drug resistance in a doxorubicin-resistant leukaemia cell line (mouse P388/DOX). A non-cytotoxic concentration of cinchonine (10 microM) increased the sensitivity to doxorubicin of multidrug-resistant P388/DOX cells and significantly enhanced the doxorubicin-induced apoptosis and DNA fragmentation in resistant cells, but had no effect in parent cells. Time-course studies demonstrated that DNA fragmentation was present 24 h after incubation with doxorubicin and cinchonine, indicating that DNA degradation was a preceding event. In cultured cells, cinchonine increased the intracellular accumulation of doxorubicin in the resistant cells in a dose-dependent manner. Using flow cytometry to measure the inhibition of the P-glycoprotein (P-gp) dependent efflux of rhodamine 123, cinchonine was found to be considerably more effective than quinine. The results with cinchonine suggest that there may be quinine derivatives with a similar capacity to inhibit drug transport by P-gp. Additionally, the G2/M phase cell population in resistant cells is increased by doxorubicin/cinchonine treatment. Exposure of resistant cells to 1 microM doxorubicin and 10 microM cinchonine resulted in the expression of Fas (APO-1/CD95) in cells after 6 h. These studies demonstrate that the cell killing effects of doxorubicin and cinchonine in resistant cells
Furusawa
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Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical University, Sendai, Japan. furusawa@tohoku-pharm.ac.jp
Nakano
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Wu
J
J
Sakaguchi
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Takayanagi
M
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Sasaki
K I
KI
Satoh
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D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002930:Cinchona Alkaloids / Q000494:pharmacology* / Q000633:toxicity; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity; D053938:DNA Fragmentation / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D018432:Drug Resistance, Multiple; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000096:biosynthesis
D000970:Antineoplastic Agents; D002930:Cinchona Alkaloids; D019014:fas Receptor; D020112:Rhodamine 123; D004317:Doxorubicin; D002945:Cisplatin; C010086:cinchonine