The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells.

Abstract

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
• Journal: Blood (Blood) Vol. 116 Issue 18 Pg. 3593-603 (Nov 04 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20644115 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antiparasitic Agents
• Chlorides
• Reactive Oxygen Species
• Cytarabine
• Ivermectin
• Calcium
• Daunorubicin

Topics

• 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