Paclitaxel- and vincristine-induced neurotoxicity and drug transport in sensory neurons

Chemotherapy-induced peripheral neuropathy (CIPN) constitutes a significant health problem due to the increasing prevalence and the lack of therapies for treatment and prevention. Patients with CIPN primarily present with sensory symptoms, such as sensory disturbances that may progress to neuropathic pain in hands and feet. While pivotal for routine cancer treatment, paclitaxel and vincristine frequently cause CIPN and impact the quality of life among cancer patients and survivors. We utilized a model of human sensory neurons derived from induced pluripotent stem cells (iPSC-SNs) to provide mechanistic understanding of CIPN caused by paclitaxel and vincristine. The morphological phenotype of iPSC-SNs following paclitaxel exposure was characterized by retraction and thickening of axons 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 ). Inhibition of P-gp and MRP1 in iPSC-SNs exacerbated neurotoxicity of paclitaxel and vincristine respectively. We further show that pre-treatment with the P-gp inducer rifampicin alleviated chemotherapy-induced structural and transcriptional alterations in iPSC-SNs. iPSC-SNs are a valuable and robust model to study the role of efflux transporters and other mechanistic targets in CIPN. Efflux transporters play a critical role in CIPN pathogenesis as they regulate the disposition of chemotherapy to the peripheral nervous system. ### Competing Interest Statement T.B.S. has given paid lectures for Pfizer and Eisai, consulted for Pfizer, and been involved in a scientific collaboration with Novo Nordisk, unrelated to the work presented in this article. T.B.S. is an owner of the patent (WO2021043673) entitled P-gp inducers as protectors against chemotherapy-induced side effects, such as peripheral neuropathy (CIPN) and hair loss. O.P. is a shareholder of Signatope GmbH that offers assay development and service using immunoaffinity-LC-MS/MS technology. All other authors declared no conflicts of interest for this work.