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Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation.

ABSTRACT: Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy.

SUBMITTER: Cetinkaya-Fisgin A

PROVIDER: S-EPMC7736304 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation.

Cetinkaya-Fisgin Aysel A Luan Xinghua X Reed Nicole N Jeong Ye Eun YE Oh Byoung Chol BC Hoke Ahmet A

Scientific reports 20201214 1

Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in ...[more]

PMID: 33318563

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