Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress - PubMed (original) (raw)
. 2018 Feb 26;497(1):241-247.
doi: 10.1016/j.bbrc.2018.02.063. Epub 2018 Feb 8.
Affiliations
- PMID: 29428725
- DOI: 10.1016/j.bbrc.2018.02.063
Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress
Jiaqiao Wang et al. Biochem Biophys Res Commun. 2018.
Abstract
Mitochondria has been a promising target in blood cancer given their unique dependencies on mitochondrial functions compared to normal hematopoietic cells. In line with this concept, we show that an anthelminthic drug ivermectin selectively kills chronic myeloid leukemia (CML) cells via inducing mitochondrial dysfunctions and oxidative stress. Ivermectin is significantly more effective in inducing caspase-dependent apoptosis in CML cell line K562 and primary CML CD34 than normal bone marrow (NBM) CD34 cells. Ivermectin also augments in vitro and in vivo efficacy of standard CML tyrosine kinase inhibitors. Mechanistically, ivermectin inhibits respiratory complex I activity and suppresses mitochondrial respiration in K562 and CML CD34 cells. Interestingly, we demonstrate that mitochondrial respiration are lower in NBM CD34 compared to malignant CD34 cells. In addition, ivermectin also induces mitochondrial dysfunctions in NBM CD34 cells in a similar manner as in CML CD34 cells whereas NBM CD34 cells are significantly less sensitive to ivermectin than CML CD34 cells. These suggest that NBM CD34 cells are more tolerable to mitochondrial dysfunctions than CML CD34 cells. Consistently, ivermectin induces higher levels of oxidative stress and damage in CML than normal counterparts. Antioxidant NAC rescues ivermectin's effects, confirming oxidative stress as the mechanism of its action in CML. Our work provides the fundamental evidence to repurpose ivermectin for CML treatment. Our work also highlights the therapeutic value of targeting mitochondria respiration in CML.
Keywords: CML; Ivermectin; Mitochondrial respiration; Oxidative damage; Selectivity.
Copyright © 2018 Elsevier Inc. All rights reserved.
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