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

Clin Transl Sci. 2021 Jul;14(4):1490-1504. doi: 10.1111/cts.13012. Epub 2021 May 31.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / 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
  • Peripheral Nervous System Diseases / prevention & control*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Primary Cell Culture
  • Ribonucleoproteins, Small Nuclear / antagonists & inhibitors*
  • Ribonucleoproteins, Small Nuclear / genetics
  • Ribonucleoproteins, Small Nuclear / metabolism
  • Vincristine / adverse effects*
  • Vincristine / therapeutic use
  • Xenograft Model Antitumor Assays
  • Young Adult


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