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

• DOI: 10.1101/2023.02.07.527432
• Publication Date: 2023-02-08T02:05:32Z
• Authors: Christina Mortensen; Katherina C. Chua; Helen S. Hammer; Flemming Nielsen; Oliver Pötz; Åsa Fex Svenningsen; Deanna L. Kroetz; Tore Bjerregaard ...
• Keywords: Neurotoxicity

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) constitutes a significant health problem due to the increasing prevalence and lack of therapies for treatment prevention. Patients with CIPN primarily present sensory symptoms, such as disturbances that may progress neuropathic pain in hands feet. While pivotal routine cancer treatment, paclitaxel vincristine frequently cause impact quality life among patients survivors. We utilized model human neurons derived from induced pluripotent stem cells (iPSC-SNs) provide mechanistic understanding caused by vincristine. The morphological phenotype iPSC-SNs following exposure was characterized retraction thickening axons while fragmentation abolishment axons. Both agents increased mRNA expression receptor, transient receptor potential vanilloid ( TRPV1 ), highly neuronal damage, measured activating transcription factor 3 ATF3 ) mRNA. express efflux transporters, P-glycoprotein (P-gp, encoded ABCB1 multidrug resistance-associated protein 1 (MPR1, ABCC1 ). Inhibition P-gp MRP1 exacerbated neurotoxicity respectively. further show pre-treatment inducer rifampicin alleviated chemotherapy-induced structural transcriptional alterations iPSC-SNs. are valuable robust study role transporters other targets CIPN. Efflux play critical pathogenesis they regulate disposition chemotherapy nervous system.