Molsidomine provides neuroprotection against vincristine-induced peripheral neurotoxicity through soluble guanylyl cyclase activation.

ABSTRACT: Peripheral neurotoxicity is a dose-limiting adverse reaction of primary frontline chemotherapeutic agents, including vincristine. Neuropathy can be so disabling that patients drop out of potentially curative therapy, negatively impacting cancer prognosis. The hallmark of vincristine neurotoxicity is axonopathy, yet its underpinning mechanisms remain uncertain. We developed a comprehensive drug discovery platform to identify neuroprotective agents against vincristine-induced neurotoxicity. Among the hits identified, SIN-1-an active metabolite of molsidomine-prevents vincristine-induced axonopathy in both motor and sensory neurons without compromising vincristine anticancer efficacy. Mechanistically, we found that SIN-1's neuroprotective effect is mediated by activating soluble guanylyl cycl

SUBMITTER: Utkina-Sosunova I 

PROVIDER: S-EPMC11336221 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature