Document Detail


The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells.
MedLine Citation:
PMID:  20644115     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
To identify known drugs with previously unrecognized anticancer activity, we compiled and screened a library of such compounds to identify agents cytotoxic to leukemia cells. From these screens, we identified ivermectin, a derivative of avermectin B1 that is licensed for the treatment of the parasitic infections, strongyloidiasis and onchocerciasis, but is also effective against other worm infestations. As a potential antileukemic agent, ivermectin induced cell death at low micromolar concentrations in acute myeloid leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. Ivermectin also delayed tumor growth in 3 independent mouse models of leukemia at concentrations that appear pharmacologically achievable. As an antiparasitic, ivermectin binds and activates chloride ion channels in nematodes, so we tested the effects of ivermectin on chloride flux in leukemia cells. Ivermectin increased intracellular chloride ion concentrations and cell size in leukemia cells. Chloride influx was accompanied by plasma membrane hyperpolarization, but did not change mitochondrial membrane potential. Ivermectin also increased reactive oxygen species generation that was functionally important for ivermectin-induced cell death. Finally, ivermectin synergized with cytarabine and daunorubicin that also increase reactive oxygen species production. Thus, given its known toxicology and pharmacology, ivermectin could be rapidly advanced into clinical trial for leukemia.
Authors:
Sumaiya Sharmeen; Marko Skrtic; Mahadeo A Sukhai; Rose Hurren; Marcela Gronda; Xiaoming Wang; Sonali B Fonseca; Hong Sun; Tabitha E Wood; Richard Ward; Mark D Minden; Robert A Batey; Alessandro Datti; Jeff Wrana; Shana O Kelley; Aaron D Schimmer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-19
Journal Detail:
Title:  Blood     Volume:  116     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-05     Completed Date:  2010-12-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3593-603     Citation Subset:  AIM; IM    
Affiliation:
Princess Margaret Hospital, Ontario Cancer Institute, Toronto, ON, Canada.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology,  therapeutic use*
Antiparasitic Agents / pharmacology,  therapeutic use*
Calcium / metabolism
Cell Death / drug effects
Cell Line, Tumor
Cell Membrane / drug effects
Cell Size / drug effects
Cell Survival / drug effects*
Chlorides / metabolism
Cytarabine / pharmacology
Daunorubicin / pharmacology
Drug Synergism
Gene Expression Regulation, Leukemic / drug effects
Humans
Ivermectin / pharmacology,  therapeutic use*
Leukemia / drug therapy*
Mice
Mice, SCID
Reactive Oxygen Species / metabolism
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
//Canadian Institutes of Health Research
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Antiparasitic Agents; 0/Chlorides; 0/Reactive Oxygen Species; 147-94-4/Cytarabine; 20830-81-3/Daunorubicin; 70288-86-7/Ivermectin; 7440-70-2/Calcium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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