Lavie Y, Harel-Orbital T, Gaffield W, Liscovitch M
Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
Anticancer Res. 2001 Mar-Apr;21(2A):1189-94.
Intrinsic or acquired resistance of tumor cells to multiple cytotoxic drugs (multidrug resistance MDR) is a major cause of failure of cancer chemotherapy. MDR is often caused by elevated expression of drug transporters such as P-glycoprotein (P-gp) or multidrug resistance protein (MRP). A number of compounds, termed chemosensitizers, have little or no cytotoxic action of their own, but inhibit (P-gp) or MRP-mediated drug export and are capable of sensitizing MDR cells to the cytotoxic effects of chemotherapeutic drugs. Here we examined the ability of steroidal alkaloids of plant origin, namely the Veratrum sp. alkaloid cyclopamine and the Lycopersicon sp. alkaloid tomatidine, to act as potent and effective chemosensitizers in multidrug resistant tumor cells. Drug uptake was determined by measuring accumulation of tetramethylrosamine in multidrug resistant NCI AdrR human adenocarcinoma cells. Resistance to adriamycin and vinblastine was determined by utilizing the MTT cell survival assay. Cyclopamine and tomatidine elevate tetramethylrosamine uptake by NCI AdrR cells and sensitize the cells to the cytotoxic action of adriamycin and vinblastine. In both cases these agents are comparable in patency and efficacy to verapamil, a reversal agent commonly used in MDR research. It is concluded that steroidal alkaloids of plant origin act as inhibitors of P-gp-mediated drug transport and multidrug resistance and therefore may serve as chemosensitizers in combination chemotherapy with conventional cytotoxic drugs for treating multidrug resistant cancer.
肿瘤细胞对多种细胞毒性药物的内在或获得性耐药（多药耐药，MDR）是癌症化疗失败的主要原因。MDR通常由药物转运蛋白如P-糖蛋白（P-gp）或多药耐药蛋白（MRP）的表达升高引起。许多被称为化学增敏剂的化合物自身几乎没有或没有细胞毒性作用，但能抑制P-gp或MRP介导的药物外排，并能使MDR细胞对化疗药物的细胞毒性作用敏感。在此，我们研究了植物来源的甾体生物碱，即藜芦属生物碱环杷明和番茄属生物碱番茄碱，在多药耐药肿瘤细胞中作为强效且有效的化学增敏剂的能力。通过测量四甲基罗丹明在多药耐药的NCI AdrR人腺癌细胞中的积累来确定药物摄取。利用MTT细胞存活试验确定对阿霉素和长春碱的耐药性。环杷明和番茄碱可提高NCI AdrR细胞对四甲基罗丹明的摄取，并使细胞对阿霉素和长春碱的细胞毒性作用敏感。在这两种情况下，这些药物在通畅性和功效方面与维拉帕米相当，维拉帕米是MDR研究中常用的一种逆转剂。得出的结论是，植物来源的甾体生物碱可作为P-gp介导的药物转运和多药耐药的抑制剂，因此在与传统细胞毒性药物联合化疗治疗多药耐药癌症时可作为化学增敏剂。
