Clinical Pharmacology, Pharmacy, and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
Neuropharmacology. 2024 Nov 1;258:110062. doi: 10.1016/j.neuropharm.2024.110062. Epub 2024 Jul 5.
and Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) constitutes a significant health problem due to the increasing prevalence and lack of therapies for treatment and prevention. While pivotal for routine cancer treatment, paclitaxel and vincristine frequently cause CIPN and impact the quality of life among cancer patients and survivors. Here, we investigate molecular mechanisms and drug transport in CIPN.
Human sensory neurons were derived from induced pluripotent stem cells (iPSC-SNs), which were characterized using flow cytometry and immunolabeling. These iPSC-SNs were exposed to different concentrations of the two microtubule-targeting agents, paclitaxel and vincristine, with and without pre-exposure to inhibitors and inducers of efflux transporters. Neuronal networks were quantified via fluorescent staining against sensory neuron markers. Transcriptional effects of the chemotherapeutics were examined using quantitative polymerase chain reactions (qPCR).
Paclitaxel exposure resulted in axonal retraction and thickening, while vincristine caused fragmentation and abolishment of axons. Both agents increased the mRNA expression of the pain receptor, transient receptor potential vanilloid (TRPV1), and highly induced neuronal damage, as measured by activating transcription factor 3 (ATF3) mRNA. iPSC-SNs express the efflux transporters, P-glycoprotein (P-gp, encoded by ABCB1) and multidrug resistance-associated protein 1 (MPR1, encoded by ABCC1). Modulation of efflux transporters indicate that P-gp and MRP1 play a role in modulating neuronal accumulation and neurotoxicity in preliminary experiments.
and Implications: iPSC-SNs are a valuable and robust model to study the role of efflux transporters and other mechanistic targets in CIPN. Efflux transporters may play a role in CIPN pathogenesis as they regulate the disposition of chemotherapy to the peripheral nervous system, and they may present potential therapeutic targets for CIPN.
化疗引起的周围神经病变（CIPN）是一个严重的健康问题，因为其发病率不断上升，且缺乏治疗和预防方法。紫杉醇和长春新碱在常规癌症治疗中至关重要，但它们常引起 CIPN，并影响癌症患者和幸存者的生活质量。在这里，我们研究 CIPN 的分子机制和药物转运。
我们从诱导多能干细胞（iPSC-SN）中获得人感觉神经元，并用流式细胞术和免疫标记法对其进行鉴定。将这些 iPSC-SN 暴露于不同浓度的两种微管靶向药物，紫杉醇和长春新碱，以及在没有预先暴露于外排转运蛋白的抑制剂和诱导剂的情况下进行暴露。通过针对感觉神经元标志物的荧光染色来量化神经元网络。使用定量聚合酶链反应（qPCR）检查化疗药物的转录效应。
紫杉醇暴露导致轴突回缩和变厚，而长春新碱导致轴突碎片化和消失。两种药物都增加了疼痛受体瞬时受体电位香草酸（TRPV1）的 mRNA 表达，并通过激活转录因子 3（ATF3）mRNA 高度诱导神经元损伤。iPSC-SN 表达外排转运蛋白，P-糖蛋白（由 ABCB1 编码）和多药耐药相关蛋白 1（由 ABCC1 编码）。外排转运蛋白的调节表明 P-糖蛋白和 MRP1 在初步实验中在调节神经元积累和神经毒性方面发挥作用。
iPSC-SN 是研究外排转运蛋白和 CIPN 中其他机制靶点作用的有价值且强大的模型。外排转运蛋白可能在 CIPN 发病机制中发挥作用，因为它们调节化疗药物在周围神经系统中的处置，并且它们可能是 CIPN 的潜在治疗靶点。
