Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, New York, United States of America.
PLoS One. 2011 Apr 28;6(4):e19329. doi: 10.1371/journal.pone.0019329.
One of the major causes of chemotherapy failure in cancer treatment is multidrug resistance (MDR) which is mediated by the ABCB1/P-glycoprotein. Previously, through the use of an extensive screening process, we found that vardenafil, a phosphodiesterase 5 (PDE-5) inhibitor significantly reverses MDR in ABCB1 overexpressing cancer cells, and its efficacy was greater than that of tadalafil, another PDE-5 inhibitor. The present study was designed to determine the reversal mechanisms of vardenafil and tadalafil on ABC transporters-mediated MDR. Vardenafil or tadalafil alone, at concentrations up to 20 µM, had no significant toxic effects on any of the cell lines used in this study, regardless of their membrane transporter status. However, vardenafil when used in combination with anticancer substrates of ABCB1, significantly potentiated their cytotoxicity in ABCB1 overexpressing cells in a concentration-dependent manner, and this effect was greater than that of tadalafil. The sensitivity of the parenteral cell lines to cytotoxic anticancer drugs was not significantly altered by vardenafil. The differential effects of vardenafil and tadalafil appear to be specific for the ABCB1 transporter as both vardenafil and tadalafil had no significant effect on the reversal of drug resistance conferred by ABCC1 (MRP1) and ABCG2 (BCRP) transporters. Vardenafil significantly increased the intracellular accumulation of [(3)H]-paclitaxel in the ABCB1 overexpressing KB-C2 cells. In addition, vardenafil significantly stimulated the ATPase activity of ABCB1 and inhibited the photolabeling of ABCB1 with [(125)I]-IAAP. Furthermore, Western blot analysis indicated the incubation of cells with either vardenafil or tadalafil for 72 h did not alter ABCB1 protein expression. Overall, our results suggest that vardenafil reverses ABCB1-mediated MDR by directly blocking the drug efflux function of ABCB1.
癌症治疗中化疗失败的一个主要原因是多药耐药性（MDR），它是由 ABCB1/P-糖蛋白介导的。此前，通过广泛的筛选过程，我们发现，磷酸二酯酶 5（PDE-5）抑制剂伐地那非显著逆转了 ABCB1 过表达癌细胞的 MDR，其疗效优于另一种 PDE-5 抑制剂他达拉非。本研究旨在确定伐地那非和他达拉非对 ABC 转运体介导的 MDR 的逆转机制。伐地那非或他达拉非单独使用，浓度高达 20 μM，对本研究中使用的任何细胞系均无明显的毒性作用，无论其膜转运体状态如何。然而，伐地那非与 ABCB1 的抗癌底物联合使用时，以浓度依赖的方式显著增强了 ABCB1 过表达细胞中的细胞毒性，其效果大于他达拉非。亲脂性细胞系对细胞毒性抗癌药物的敏感性并未因伐地那非而显著改变。伐地那非和他达拉非的差异作用似乎是针对 ABCB1 转运体的，因为伐地那非和他达拉非对 ABCC1（MRP1）和 ABCG2（BCRP）转运体赋予的耐药性逆转均无显著影响。伐地那非显著增加了 ABCB1 过表达 KB-C2 细胞中 [(3)H]-紫杉醇的细胞内积累。此外，伐地那非显著刺激了 ABCB1 的 ATP 酶活性并抑制了 [(125)I]-IAAP 对 ABCB1 的光标记。此外，Western blot 分析表明，细胞与伐地那非或他达拉非孵育 72 h 不会改变 ABCB1 蛋白表达。总的来说，我们的结果表明，伐地那非通过直接阻断 ABCB1 的药物外排功能来逆转 ABCB1 介导的 MDR。
