Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons

TL;DR

This study identifies six new compounds that protect neurons from the toxic effects of the chemotherapy drug vincristine, offering potential treatments for chemotherapy-induced neuropathy.

Contribution

The study introduces six novel neuroprotectants identified through high-throughput screening in iPSC-derived neurons.

Findings

Six compounds showed favorable neuroprotective effects against vincristine-induced axon growth deficits.

Four of the six compounds were effective in protecting sensory neurons from vincristine toxicity.

The study used hiPSC-derived neurons to model and screen for neuroprotectants in a clinically relevant context.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient’s quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles – AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

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