Journal Article

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

Smith, Jennifer A., Woolf, Clifford J., Singh, Bhagat, Snavely, Andrew R., Zhen, Shannon, Pandey, Roshan, Barrett, Lee B., Chen, Kuchuan, Cheng, Anya, Petrova, Veselina, Splaine, Jennifer, Hermawan, Crystal

2024

Overview

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.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: adverse effects / Antineoplastic drugs / Axons / Axons - drug effects / Axons - metabolism / Axons - pathology / Biochemistry / Biomedical and Life Sciences / Biomedicine / Bone cancer / Breast cancer / breasts / Cancer / Cell Biology / Cells, Cultured / Chemotherapy / dose response / drug therapy / High-throughput screening / Human influences / Humans / Induced Pluripotent Stem Cells - cytology / Induced Pluripotent Stem Cells - drug effects / Induced Pluripotent Stem Cells - metabolism / Leukemia / Life Sciences / Motor neurons / Motor Neurons - drug effects / Motor Neurons - metabolism / Motor Neurons - pathology / Neurons / Neurons - drug effects / Neurons - metabolism / Neurons - pathology / Neuroprotection / Neuroprotective Agents - pharmacology / Neurotoxicity / Original / Original Article / patients / peripheral nervous system diseases / Peripheral Nervous System Diseases - chemically induced / Peripheral Nervous System Diseases - drug therapy / Peripheral Nervous System Diseases - pathology / Peripheral neuropathy / Pharmacology / Pluripotency / Quality of life / Reagents / Sensory neurons / Stem cells / Toxicity / Vincristine / Vincristine - pharmacology