Gate L, Couvreur P, Nguyen-Ba G, Tapiero H
UMR-CNRS 8612, Faculty of Pharmacy, University of Paris XI, 92290 Chatenay-Malabry cedex, France.
Biomed Pharmacother. 2003 Sep;57(7):301-8. doi: 10.1016/s0753-3322(03)00037-4.
Anthracyclines are the most commonly used classes of anticancer agents in chemotherapy. Development of resistance to these molecules is one of the major reasons for treatment failure. The overexpression of the membrane transporter P-glycoprotein (P-gp) is among the principal mechanisms involved in this phenomenon. This pump, which is responsible for the multidrug resistance (MDR) phenotype, decreases the toxicity of a wide range of unrelated anticancer drugs by increasing their cellular efflux. Structure-activity relationship experiments have shown that the positively charged amino group of the anthracyclines could be responsible for their transport by P-gp. Here, we used three new anthracyclines that shared the same chromophore but differed by the degree of N-methylation of their sugar moiety. Oxaunomycin (OXN) possessed a non-methylated amino group, while LB-1 was monomethylated and beta-clamycin T (BCT) was dimethylated. In sensitive cells (FLC), reduced cytotoxicity was related to the level of N-methylation; whereas in resistant cells (DOX-RFLC(1) and DOX-RFLC(2)) overexpressing different levels of P-gp, increased N-methylation enhanced anthracycline cytotoxicity. Decreased resistance in DOX-RFLCs was associated with an increased drug accumulation due to a reduced cellular efflux. As expected, the MDR modulator verapamil decreased resistance to these anthracyclines by increasing the cellular accumulation. These results suggest that N-methylation of anthracyclines circumvents resistance by diminishing drug transport by P-gp in MDR-positive cells. These observations could be the consequence of the steric hindrance created by the methyl group(s) which may impair the interaction between the positively charged amino group and the active site of P-gp.
蒽环类药物是化疗中最常用的抗癌药物类别。对这些分子产生耐药性是治疗失败的主要原因之一。膜转运蛋白P-糖蛋白（P-gp）的过表达是参与这一现象的主要机制之一。这种负责多药耐药（MDR）表型的泵，通过增加细胞外排来降低多种不相关抗癌药物的毒性。构效关系实验表明，蒽环类药物带正电荷的氨基可能是其被P-gp转运的原因。在此，我们使用了三种新的蒽环类药物，它们具有相同的发色团，但糖部分的N-甲基化程度不同。氧阿霉素（OXN）具有未甲基化的氨基，而LB-1是单甲基化的，β-克拉霉素T（BCT）是二甲基化的。在敏感细胞（FLC）中，细胞毒性降低与N-甲基化水平有关；而在过表达不同水平P-gp的耐药细胞（DOX-RFLC(1)和DOX-RFLC(2)）中，N-甲基化增加增强了蒽环类药物的细胞毒性。DOX-RFLC细胞中耐药性的降低与细胞外排减少导致的药物积累增加有关。正如预期的那样，MDR调节剂维拉帕米通过增加细胞内药物积累降低了对这些蒽环类药物的耐药性。这些结果表明，蒽环类药物的N-甲基化通过减少MDR阳性细胞中P-gp介导的药物转运来规避耐药性。这些观察结果可能是甲基产生的空间位阻的结果，甲基可能会损害带正电荷的氨基与P-gp活性位点之间的相互作用。
