Shibata H, Furusawa S, Kawauchi H, Sasaki K, Takayanagi Y
Cancer Research Institute, Tohoku College of Pharmacy, Sendai, Japan.
Nihon Yakurigaku Zasshi. 1991 Jul;98(1):1-6. doi: 10.1254/fpj.98.1_1.
The activity of reserpine and a possible mechanism by which it reverses the resistance to both doxorubicin and pirarubicin in doxorubicin-resistant P388 leukemia (P388/DOX) cells were examined in vitro. During 48 hr drug-exposure, the sensitivity of doxorubicin and pirarubicin were potentiated markedly when reserpine was present at the concentration of 1 microgram/ml, which is not toxic to P388 leukemia (P388/S) cells. However, reserpine had little effect on the cytotoxicity of doxorubicin and pirarubicin in the sensitive parent cell. Reserpine at 0.5-20 micrograms/ml increased intracellular accumulation of doxorubicin and pirarubicin in the drug-resistant cells. The potentiating action of reserpine was stronger when the cells were preincubated with reserpine within 30 min. Efflux of doxorubicin and pirarubicin was greater in drug-resistant cells compared to sensitive cells. This enhanced efflux of drug resulted in a decrease in the intracellular accumulation of doxorubicin in the drug-resistant cells. When the resistant cells were exposed to 2 micrograms/ml of reserpine, this enhanced efflux was blocked. A similar effect of reserpine on doxorubicin was seen with the efflux pattern of pirarubicin. From the measurements of drug uptake and efflux, it seems that like other multiple drug resistance modifiers, reserpine modulates anthracycline resistance by increasing intracellular accumulation of drug.
在体外研究了利血平的活性及其逆转多柔比星耐药的P388白血病（P388/DOX）细胞对多柔比星和吡柔比星耐药性的可能机制。在48小时的药物暴露期间，当利血平以1微克/毫升的浓度存在时，多柔比星和吡柔比星的敏感性显著增强，该浓度对P388白血病（P388/S）细胞无毒。然而，利血平对敏感亲本细胞中多柔比星和吡柔比星的细胞毒性几乎没有影响。0.5-20微克/毫升的利血平增加了耐药细胞中多柔比星和吡柔比星的细胞内蓄积。当细胞在30分钟内用利血平预孵育时，利血平的增强作用更强。与敏感细胞相比，耐药细胞中多柔比星和吡柔比星的外排更大。这种药物外排的增强导致耐药细胞中多柔比星的细胞内蓄积减少。当耐药细胞暴露于2微克/毫升的利血平时，这种增强的外排被阻断。利血平对吡柔比星的外排模式也有类似的作用。从药物摄取和外排的测量结果来看，似乎与其他多药耐药调节剂一样，利血平通过增加药物的细胞内蓄积来调节蒽环类药物耐药性。
