Roles of sildenafil in enhancing drug sensitivity in cancer.
Roles of sildenafil in enhancing drug sensitivity in cancer.
复制标题
DOI：
10.1158/0008-5472.can-11-0375
复制
发表时间：
2011-06-01
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;Patel AS;Fu LW;Chen ZS
肿瘤多药耐药（multidrug resistance，MDR）现象的出现降低了肿瘤化疗成功的希望。ATP结合盒转运蛋白超家族是最大的跨膜转运蛋白家族。ABC转运蛋白的过表达是体内外肿瘤细胞MDR的主要决定因素。不幸的是，直到最近，大多数用于克服ABC转运蛋白介导的MDR的策略都取得了有限的成功。MDR的理想调节剂是具有低倾向性诱导毒性和改变MDR药物的药代动力学特征的调节剂。西地那非（Viagra®）是cGMP特异性磷酸二酯酶5型（PDE 5）的抑制剂，可显著逆转ABC转运蛋白介导的MDR。我们的研究结果表明，西地那非对ABC转运蛋白有不同的抑制作用，它显着降低ABCB 1和ABCG 2的外排活性，但对ABCC 1没有显着影响。新出现的证据表明，西地那非和其他PDE 5抑制剂可能会增强某些类型的癌症对标准化疗药物的敏感性。
The phenomenon of multidrug resistance (MDR) has decreased the hope for successful cancer chemotherapy. The ATP-binding cassette (ABC) transporter super-family is the largest transmembrane family. The overexpression of ABC transporters is a major determinant of MDR in cancer cells both in vitro and in vivo. Unfortunately, until recently, most of the strategies used to surmount ABC transporter-mediated MDR have had limited success. An ideal modulator of MDR would be one that has a low liability to induce toxicity and alter the pharmacokinetic profile of antineoplastic drugs. Sildenafil (Viagra®), an inhibitor of cGMP-specific phosphodiesterase types 5 (PDE5) was found to significantly reverse ABC-transporters-mediated MDR. Our results indicated that sildenafil had differential inhibitory effects on ABC transporters; it significantly decreased the efflux activity of ABCB1 and ABCG2, but had no significant effects on ABCC1. Emerging evidence indicates that sildenafil and other PDE5 inhibitors may enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs.