| The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. | |
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MedLine Citation:
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PMID: 20644115 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-19 |
Journal Detail:
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Title: Blood Volume: 116 ISSN: 1528-0020 ISO Abbreviation: Blood Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-11-05 Completed Date: 2010-12-15 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7603509 Medline TA: Blood Country: United States |
Other Details:
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Languages: eng Pagination: 3593-603 Citation Subset: AIM; IM |
Affiliation:
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Princess Margaret Hospital, Ontario Cancer Institute, Toronto, ON, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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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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