Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D'Youville College, Buffalo, New York, USA.
J Clin Invest. 2018 Feb 1;128(2):816-825. doi: 10.1172/JCI96160. Epub 2018 Jan 16.
Paclitaxel is among the most widely used anticancer drugs and is known to cause a dose-limiting peripheral neurotoxicity, the initiating mechanisms of which remain unknown. Here, we identified the murine solute carrier organic anion-transporting polypeptide B2 (OATP1B2) as a mediator of paclitaxel-induced neurotoxicity. Additionally, using established tests to assess acute and chronic paclitaxel-induced neurotoxicity, we found that genetic or pharmacologic knockout of OATP1B2 protected mice from mechanically induced allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes. The function of this transport system was inhibited by the tyrosine kinase inhibitor nilotinib through a noncompetitive mechanism, without compromising the anticancer properties of paclitaxel. Collectively, our findings reveal a pathway that explains the fundamental basis of paclitaxel-induced neurotoxicity, with potential implications for its therapeutic management.
紫杉醇是应用最广泛的抗癌药物之一，已知会引起剂量限制的周围神经毒性，但其起始机制尚不清楚。在这里，我们鉴定出鼠溶质载体有机阴离子转运多肽 B2（OATP1B2）是紫杉醇诱导神经毒性的介质。此外，使用评估急性和慢性紫杉醇诱导神经毒性的既定测试，我们发现 OATP1B2 的基因或药理学敲除可保护小鼠免受机械诱导的痛觉过敏、热痛觉过敏和数字最大动作电位幅度的变化。该转运系统的功能被酪氨酸激酶抑制剂尼罗替尼通过非竞争性机制抑制，而不损害紫杉醇的抗癌特性。总的来说，我们的研究结果揭示了一条解释紫杉醇诱导神经毒性的基本途径，这可能对其治疗管理具有重要意义。
