Mechanisms of peripheral neurotoxicity associated with four chemotherapy drugs using human induced pluripotent stem cell-derived peripheral neurons. (December 2021)

• Record Type: Journal Article
• Authors: Wang, Meiting; Wang, Jiaxian; Tsui, Alex Y.P.; Li, Zhaomin; Zhang, Yizhe; Zhao, Qi; Xing, Hongyan; Wang, Xijie
• Is Part Of: Toxicology in vitro. Volume 77(2022)
• Publication Date: 2021-12
• Subjects: Human induced pluripotent stem cell -- Chemotherapy drugs -- Chemotherapy-induced peripheral neurotoxicity -- Mechanism -- In vitro models; BDNF brain-derived neurotrophic factor -- Brn3a peripheral neuron subtype specifiers POU4 -- CIPN chemotherapy-induced peripheral neurotoxicity -- CGRP calcitonin gene related-peptide -- DRG dorsal root ganglia -- hESCs human embryonic stem cells -- hiPSCs human induced pluripotent stem cells -- hiPSC-PNs hiPSC-derived peripheral neurons -- Isl1 ISL LIM Homeobox -- Nav sodium channels -- NGF nerve growth factor -- PBMCs peripheral blood mononuclear cells -- PC12 pheochromocytoma cells -- SH-SY5Y human neuroblastoma cells -- SP substance P -- TKI tyrosine kinase inhibitor -- TRP transient receptor potential -- TRPM8 TRP melastatin -- TRPV1 TRP vanilloid -- Tuj-1 neuron-specific class III beta-tubulin -- 5-FU 5-Fluoro-2′-deoxyuridine; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2021.105233
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: The awareness of the long-term toxicities of cancer survivors after chemotherapy treatment has been gradually strengthened as the population of cancer survivors grows. Generally, chemotherapy-induced peripheral neurotoxicity (CIPN) is studied by animal models which are not only expensive and time-consuming, but also species-specific differences. The generation of human induced pluripotent stem cells (hiPSCs) and differentiation of peripheral neurons have provided an in vitro model to elucidate the risk of CIPN. Here, we developed a drug-induced peripheral neurotoxicity model using hiPSC-derived peripheral neurons (hiPSC-PNs) to study the mechanisms of different chemotherapeutic agents on neuronal viability using LDH assay, a cell apoptosis assay determined by caspase 3/7 activation, neurite outgrowth, ion channel expression and neurotransmitter release following treatment of cisplatin, bortezomib, ixabepilone, or pomalidomide. Our data showed that the multiple endpoints of the hiPSC-PNs model had different sensitivity to various chemotherapeutic agents. Furthermore, the chemotherapeutics separated cell viability from the decrease in neurite lengthand changed levels of ion channels and neurotransmitters to a certain extent. Thus, we study the mechanisms of peripheral neurotoxicity induced by chemotherapeutic agents through changes in these indicators. Highlights: hiPSC-PNs can be used as a novel tool to study the mechanism of neurotoxicity. hiPSC-PNs model is sensitive to chemotherapy drugs associated with CIPN. Chemotherapy drugs can influence expression of Nav1.7, TRPV1 and TRPM8. Chemotherapy drugs can influence SP and CGRP releases.