Open AccessIdentification of small molecules that mitigate vincristine‐induced neurotoxicity while sensitizing leukemia cells to vincristine
Author(s) -
Diouf Barthelemy,
Wing Claudia,
Panetta John C.,
Eddins Donnie,
Lin Wenwei,
Yang Wenjian,
Fan Yiping,
Pei Deqing,
Cheng Cheng,
Delaney Shan M.,
Zhang Wei,
Bonten Erik J.,
Crews Kristine R.,
Paugh Steven W.,
Li Lie,
Freeman Burgess B.,
Autry Robert J.,
Beard Jordan A.,
Ferguson Daniel C.,
Janke Laura J.,
Ness Kirsten K.,
Chen Taosheng,
Zakharenko Stanislav S.,
Jeha Sima,
Pui ChingHon,
Relling Mary V.,
Eileen Dolan M.,
Evans William E.
Publication year - 2021
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.13012
Subject(s) - vincristine , neurotoxicity , medicine , peripheral neuropathy , leukemia , cytotoxicity , pharmacology , toxicity , concomitant , chemotherapy , cancer research , oncology , in vitro , cyclophosphamide , endocrinology , biology , biochemistry , diabetes mellitus
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.