Sildenafil reverses ABCB1- and ABCG2-mediated chemotherapeutic drug resistance.
Sildenafil reverses ABCB1- and ABCG2-mediated chemotherapeutic drug resistance.
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DOI：
10.1158/0008-5472.can-10-3820
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Chen ZS
中科院分区：
文献类型：
--
作者：
Shi Z;Tiwari AK;Shukla S;Robey RW;Singh S;Kim IW;Bates SE;Peng X;Abraham I;Ambudkar SV;Talele TT;Fu LW;Chen ZS
西地那非是5型cGMP特异性磷酸二酯酶的有效和选择性抑制剂，临床上用于治疗勃起功能障碍和肺动脉高压。在这里，我们报告西地那非对细胞表面ABC转运蛋白（如ABCB 1、ABCC 1和ABCG 2）具有不同的作用，这些转运蛋白可调节室内和细胞内化疗药物的浓度。在ABCB 1过表达细胞中，无毒剂量的西地那非可抑制耐药性，并增加ABCB 1底物药物（如紫杉醇）的有效细胞内浓度。类似地，在ABCG 2过表达细胞中，西地那非抑制对ABCG 2底物抗癌药物的耐药性，例如，增加米托蒽醌或荧光化合物BODIPY-哌唑嗪的有效细胞内浓度。西地那非还中度抑制ABCG 2转运蛋白转运E217βG和甲氨蝶呤。机制研究表明，西地那非刺激ABCB 1 ATP酶活性并抑制[125 I]-IAAP光标记ABCB 1，而它仅轻微刺激ABCG 2 ATP酶活性并抑制[125 I]-IAAP光标记ABCG 2。相比之下，西地那非并没有改变亲本ABCB 1或ABCG 2过表达细胞对非ABCB 1和非ABCG 2底物药物的敏感性，也没有影响另一种ABC药物转运蛋白ABCC 1的功能。同源建模预测西地那非在ABCB 1跨膜区的大空腔内的结合构象。总体而言，我们发现西地那非抑制ABCB 1和ABCG 2的转运蛋白功能，对ABCB 1的作用更强。我们的研究结果表明，通过联合使用具有已知副作用和药物相互作用的临床批准药物，可以提高抗癌药物的分布和潜在活性。
Sildenafil is a potent and selective inhibitor of the type 5 cGMP-specific phosphodiesterase that is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. Here we report that sildenafil has differential effects on cell surface ABC transporters such as ABCB1, ABCC1 and ABCG2 that modulate intracompartmental and intracellular concentrations of chemotherapeutic drugs. In ABCB1-overexpressing cells, non-toxic doses of sildenafil inhibited resistance and increased the effective intracellular concentration of ABCB1 substrate drugs, such as paclitaxel. Similarly, in ABCG2-overexpressing cells, sildenafil inhibited resistance to ABCG2 substrate anticancer drugs, for example, increasing the effective intracellular concentration of mitoxantrone or the fluorescent compound BODIPY-prazosin. Sildenafil also moderately inhibited the transport of E217βG and methotrexate by the ABCG2 transporter. Mechanistic investigations revealed that sildenafil stimulated ABCB1 ATPase activity and inhibited photolabeling of ABCB1 with [125I]-IAAP, whereas it only slightly stimulated ABCG2 ATPase activity and inhibited photolabeling of ABCG2 with [125I]-IAAP. In contrast, Sildenafil did not alter the sensitivity of parental, ABCB1- or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drugs, nor did sildenafil affect the function of another ABC drug transporter ABCC1. Homology modeling predicted the binding conformation of sildenafil within the large cavity of the transmembrane region of ABCB1. Overall, we found that sildenafil inhibits the transporter function of ABCB1 and ABCG2, with a stronger effect on ABCB1. Our findings suggest a possible strategy to enhance the distribution and potentially the activity of anti-cancer drugs by jointly using a clinically approved drug with known side effects and drug-drug interactions.