Shukla Suneet, Robey Robert W, Bates Susan E, Ambudkar Suresh V
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256, USA.
Drug Metab Dispos. 2009 Feb;37(2):359-65. doi: 10.1124/dmd.108.024612. Epub 2008 Oct 29.
Sunitinib malate (Sutent, SU11248) is a small-molecule receptor tyrosine kinase inhibitor that inhibits cellular signaling of multiple targets such as the platelet-derived growth factor receptors and the vascular endothelial growth factor receptors and is used in the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Because tyrosine kinase inhibitors are known to increase the p.o. bioavailability and brain penetration of chemotherapy drugs in animal models, we sought to examine the effect of sunitinib on the ATP-binding cassette (ABC) drug transporters P-glycoprotein (P-gp, ABCB1), the multidrug resistance-associated protein 1 (ABCC1), and ABCG2, which are known to transport a wide variety of anticancer drugs. In this study, we show that sunitinib inhibits P-gp- and ABCG2-mediated efflux of fluorescent substrates in cells overexpressing these transporters. In 4-day cytotoxicity assays, at a nontoxic concentration (2 microM) sunitinib was able to partially reverse drug resistance mediated by P-gp and completely reverse resistance mediated by ABCG2. We further show a direct interaction of sunitinib with the substrate binding pocket of these transporters as it inhibited binding of the photoaffinity substrate [(125)I]iodoarylazidoprazosin to P-gp (IC(50) = 14.2 microM) and ABCG2 (IC(50) = 1.33 microM). Sunitinib stimulated the ATP hydrolysis by both transporters in a concentration-dependent manner. Conformation-sensitive antibody binding assays with the P-gp- and ABCG2-specific antibodies, UIC2 and 5D3, respectively, also confirmed the interaction of sunitinib with these transporters. Taken together, this is the first report showing that sunitinib inhibits transport mediated by ABC drug transporters, which may affect the bioavailability of drugs coadministered with sunitinib.
苹果酸舒尼替尼(索坦,SU11248)是一种小分子受体酪氨酸激酶抑制剂,可抑制多种靶点的细胞信号传导,如血小板衍生生长因子受体和血管内皮生长因子受体,用于治疗肾细胞癌和对伊马替尼耐药的胃肠道间质瘤。由于已知酪氨酸激酶抑制剂可提高动物模型中化疗药物的口服生物利用度和脑渗透率,我们试图研究舒尼替尼对ATP结合盒(ABC)药物转运体P-糖蛋白(P-gp,ABCB1)、多药耐药相关蛋白1(ABCC1)和ABCG2的影响,这些转运体已知可转运多种抗癌药物。在本研究中,我们表明舒尼替尼可抑制过表达这些转运体的细胞中P-gp和ABCG2介导的荧光底物外排。在为期4天的细胞毒性试验中,在无毒浓度(2 microM)下,舒尼替尼能够部分逆转P-gp介导的耐药性,并完全逆转ABCG2介导的耐药性。我们进一步表明舒尼替尼与这些转运体的底物结合口袋直接相互作用,因为它抑制了光亲和性底物[(125)I]碘芳基叠氮哌唑嗪与P-gp(IC(50)=14.2 microM)和ABCG2(IC(50)=1.33 microM)的结合。舒尼替尼以浓度依赖的方式刺激这两种转运体的ATP水解。分别用P-gp和ABCG2特异性抗体UIC2和5D3进行的构象敏感抗体结合试验也证实了舒尼替尼与这些转运体的相互作用。综上所述,这是第一份表明舒尼替尼抑制ABC药物转运体介导的转运的报告,这可能会影响与舒尼替尼联合使用的药物的生物利用度。