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

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, Robert J. Autry, Jordan A. Beard, Daniel C. Ferguson, Laura J. JankeKirsten K. Ness, Taosheng Chen, Stanislav S. Zakharenko, Sima Jeha, Ching Hon Pui, Mary V. Relling, M. Eileen Dolan, William E. Evans*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1490-1504
Number of pages15
JournalClinical and Translational Science
Volume14
Issue number4
DOIs
StatePublished - Jul 2021

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Neuroscience
  • Pharmacology, Toxicology and Pharmaceutics(all)

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