Identification of small molecules that mitigate vincristine-induced neurotoxicity while sensitizing leukemia cells to vincristine.

Abstract

Vincristine (VCR) is one of the most widely prescribed medications for treating solid tumors and acute lymphoblastic leukemia (ALL) in children and adults. However, its major dose-limiting toxicity is peripheral neuropathy that can disrupt curative therapy. Peripheral neuropathy can also persist into adulthood, compromising quality of life of childhood cancer survivors. Reducing VCR-induced neurotoxicity without compromising its anticancer effects would be ideal. Here, we show that low expression of NHP2L1 is associated with increased sensitivity of primary leukemia cells to VCR, and that concomitant administration of VCR with inhibitors of NHP2L1 increases VCR cytotoxicity in leukemia cells, prolongs survival of ALL xenograft mice, but decreases VCR effects on human-induced pluripotent stem cell-derived neurons and mitigates neurotoxicity in mice. These findings offer a strategy for increasing VCR's antileukemic effects while reducing peripheral neuropathy in patients treated with this widely prescribed medication.

• Authors: Barthelemy Diouf, Claudia Wing, John C Panetta, Donnie Eddins, Wenwei Lin, Wenjian Yang, Yiping Fan, Deqing Pei, Cheng Cheng, Shannon M Delaney, Wei Zhang, Erik J Bonten, Kristine R Crews, Steven W Paugh, Lie Li, Burgess B Freeman 3rd, Robert J Autry, Jordan A Beard, Daniel C Ferguson, Laura J Janke, Kirsten K Ness, Taosheng Chen, Stanislav S Zakharenko, Sima Jeha, Ching-Hon Pui, Mary V Relling, M Eileen Dolan, William E Evans
• Journal: Clinical and translational science (Clin Transl Sci) Vol. 14 Issue 4 Pg. 1490-1504 (07 2021) ISSN: 1752-8062 [Electronic] United States
• PMID: 33742760 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Ribonucleoproteins, Small Nuclear
• Snu13 protein, human
• Vincristine

Topics

• Adolescent
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Cells, Cultured
• Child
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression Regulation, Leukemic
• Gene Knockdown Techniques
• Humans
• Induced Pluripotent Stem Cells
• Male
• Mice
• Neurons
• Peripheral Nervous System Diseases (chemically induced, prevention & control)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, pathology)
• Primary Cell Culture
• Ribonucleoproteins, Small Nuclear (antagonists & inhibitors, genetics, metabolism)
• Vincristine (adverse effects, therapeutic use)
• Xenograft Model Antitumor Assays
• Young Adult