Zhang Guan-Nan, Zhang Yun-Kai, Wang Yi-Jun, Barbuti Anna Maria, Zhu Xi-Jun, Yu Xin-Yue, Wen Ai-Wen, Wurpel John N D, Chen Zhe-Sheng
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences,St. John's University, Queens, New York, 11439, USA.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences,St. John's University, Queens, New York, 11439, USA; The Affiliated High School of South China Normal University, Guangzhou, Guangdong, 510630, China.
Pharmacol Res. 2017 May;119:89-98. doi: 10.1016/j.phrs.2017.01.024. Epub 2017 Jan 25.
Cabozantinib (XL184) is a small molecule tyrosine kinase receptor inhibitor, which targets c-Met and VEGFR2. Cabozantinib has been approved by the Food and Drug Administration to treat advanced medullary thyroid cancer and renal cell carcinoma. In the present study, we evaluated the ability of cabozantinib to modulate the function of the ATP-binding cassette subfamily G member 2 (ABCG2) by sensitizing cells that are resistant to ABCG2 substrate antineoplastic drugs. We used a drug-selected resistant cell line H460/MX20 and three ABCG2 stable transfected cell lines ABCG2-482-R2, ABCG2-482-G2, and ABCG2-482-T7, which overexpress ABCG2. Cabozantinib, at non-toxic concentrations (3 or 5μM), sensitized the ABCG2-overexpressing cells to mitoxantrone, SN-38, and topotecan. Our results indicate that cabozantinib reverses ABCG2-mediated multidrug resistance by antagonizing the drug efflux function of the ABCG2 transporter instead of downregulating its expression. The molecular docking analysis indicates that cabozantinib binds to the drug-binding site of the ABCG2 transporter. Overall, our findings demonstrate that cabozantinib inhibits the ABCG2 transporter function and consequently enhances the effect of the antineoplastic agents that are substrates of ABCG2. Cabozantinib may be a useful agent in anticancer treatment regimens for patients who are resistant to ABCG2 substrate drugs.
卡博替尼（XL184）是一种小分子酪氨酸激酶受体抑制剂，其作用靶点为c-Met和VEGFR2。卡博替尼已获美国食品药品监督管理局批准用于治疗晚期甲状腺髓样癌和肾细胞癌。在本研究中，我们通过使对ABCG2底物抗肿瘤药物耐药的细胞敏感，评估了卡博替尼调节ATP结合盒亚家族G成员2（ABCG2）功能的能力。我们使用了一种药物筛选的耐药细胞系H460/MX20和三种过表达ABCG2的ABCG2稳定转染细胞系ABCG2-482-R2、ABCG2-482-G2和ABCG2-482-T7。卡博替尼在无毒浓度（3或5μM）下，使过表达ABCG2的细胞对米托蒽醌、SN-38和拓扑替康敏感。我们的结果表明，卡博替尼通过拮抗ABCG2转运蛋白的药物外排功能而非下调其表达来逆转ABCG2介导的多药耐药。分子对接分析表明，卡博替尼与ABCG2转运蛋白的药物结合位点结合。总体而言，我们的研究结果表明，卡博替尼抑制ABCG2转运蛋白功能，从而增强作为ABCG2底物的抗肿瘤药物的效果。对于对ABCG2底物药物耐药的患者，卡博替尼可能是抗癌治疗方案中的一种有用药物。
