Kathawala Rishil J, Wei Liuya, Anreddy Nagaraju, Chen Kang, Patel Atish, Alqahtani Saeed, Zhang Yun-Kai, Wang Yi-Jun, Sodani Kamlesh, Kaddoumi Amal, Ashby Charles R, Chen Zhe-Sheng
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA. Current address: Division of Oncology, Stanford University, Stanford, CA, USA.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA. School of Pharmacy and Biological Sciences, Weifang Medical University, Weifang, People's Republic of China.
Oncotarget. 2015 Jan 1;6(1):510-21. doi: 10.18632/oncotarget.2638.
Paclitaxel exhibits clinical activity against a wide variety of solid tumors. However, resistance to paclitaxel significantly attenuates the response to chemotherapy. The ABC transporter subfamily C member 10 (ABCC10), also known as multi-drug resistance protein 7 (MRP7) efflux transporter, is a major mediator of paclitaxel resistance. Here, we determine the effect of NVP-BHG712, a specific EphB4 receptor inhibitor, on 1) paclitaxel resistance in HEK293 cells transfected with ABCC10, 2) the growth of tumors in athymic nude mice that received NVP-BHG712 and paclitaxel systemically and 3) the pharmacokinetics of paclitaxel in presence or absence of NVP-BHG712. NVP-BHG712 (0.5 μM), in HEK293/ABCC10 cells, significantly enhanced the intracellular accumulation of paclitaxel by inhibiting the efflux activity of ABCC10 without altering the expression level of the ABCC10 protein. Furthermore, NVP-BHG712 (25 mg/kg, p.o., q3d x 6), in combination with paclitaxel (15 mg/kg, i.p., q3d x 6), significantly inhibited the growth of ABCC10-expressing tumors in athymic nude mice. NVP-BHG712 administration significantly increased the levels of paclitaxel in the tumors but not in plasma compared to paclitaxel alone. The combination of NVP-BHG712 and paclitaxel could serve as a novel and useful therapeutic strategy to attenuate paclitaxel resistance mediated by the expression of the ABCC10 transporter.
紫杉醇对多种实体瘤具有临床活性。然而，对紫杉醇的耐药性会显著削弱化疗反应。ABC转运蛋白C亚家族成员10（ABCC10），也被称为多药耐药蛋白7（MRP7）外排转运体，是紫杉醇耐药的主要介导因子。在此，我们确定了特异性EphB4受体抑制剂NVP - BHG712对以下方面的影响：1）在转染了ABCC10的HEK293细胞中的紫杉醇耐药性；2）全身接受NVP - BHG712和紫杉醇的无胸腺裸鼠体内肿瘤的生长；3）在有或无NVP - BHG712存在的情况下紫杉醇的药代动力学。在HEK293/ABCC10细胞中，NVP - BHG712（0.5 μM）通过抑制ABCC10的外排活性，在不改变ABCC10蛋白表达水平的情况下，显著增强了紫杉醇的细胞内蓄积。此外，NVP - BHG712（25 mg/kg，口服，每3天一次，共6次）与紫杉醇（15 mg/kg，腹腔注射，每3天一次，共6次）联合使用，显著抑制了无胸腺裸鼠体内表达ABCC10的肿瘤的生长。与单独使用紫杉醇相比，给予NVP - BHG712显著提高了肿瘤中紫杉醇的水平，但血浆中未提高。NVP - BHG712与紫杉醇联合使用可作为一种新的有效治疗策略，以减轻由ABCC10转运体表达介导的紫杉醇耐药性。
