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

Blood
Sumaiya SharmeenA D Schimmer

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-...Continue Reading

References

Apr 1, 1994·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·A SellaC J Logothetis
Mar 19, 1994·Lancet·J L Costa, J A Diazgranados
Jan 1, 1996·European Journal of Clinical Pharmacology·O Z BarakaJ F Williams
May 1, 1997·Journal of Environmental Science and Health. Part. B, Pesticides, Food Contaminants, and Agricultural Wastes·S HussainS F Ali
Oct 6, 2000·Medical Hypotheses·Q KongK O Lillehei
Jun 2, 2001·Parasitology·K R BrownE A Ottesen
Sep 14, 2002·Journal of Veterinary Medicine. A, Physiology, Pathology, Clinical Medicine·I MeralF B Hembrough
Oct 5, 2002·Journal of Clinical Pharmacology·Cynthia A GuzzoKenneth C Lasseter
Oct 28, 2003·The Journal of Biological Chemistry·Tianshuang LiuAntonella Casola
Mar 17, 2004·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Eric J SmallNicholas J Vogelzang
Mar 30, 2004·Biochemical and Biophysical Research Communications·Baohong JiangChiyoko Inagaki
Dec 17, 2004·Proceedings of the National Academy of Sciences of the United States of America·Alex KentsisKatherine L B Borden
Dec 20, 2005·The Journal of Membrane Biology·F LangS M Huber
Dec 20, 2005·The Journal of Membrane Biology·Karl Kunzelmann
Mar 25, 2006·The Journal of Dermatology·Kentaro YonekuraAtae Utsunomiya
Jul 6, 2006·Apoptosis : an International Journal on Programmed Cell Death·Debbie M GurfinkelAaron D Schimmer
Jan 20, 2007·Regulatory Toxicology and Pharmacology : RTP·S S DadarkarM M Gatne
Mar 17, 2007·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Eun-Jung Park, Kwangsik Park
Aug 3, 2007·Toxicology Letters·Ping ZhangBin Liu
May 1, 2008·The AAPS Journal·Aránzazu González CangaJuan J García Vieitez
Jul 16, 2008·Free Radical Biology & Medicine·Hong Sook KimMyung-Hee Chung
Aug 19, 2008·Biochemical and Biophysical Research Communications·Keith TanKatherine L B Borden
Nov 7, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Rosemary H MiltonMichele Mazzanti
Jan 21, 2009·Nature Reviews. Drug Discovery·Alan S Verkman, Luis J V Galietta
Jan 29, 2009·Annals of Tropical Medicine and Parasitology·S M AsioA W Onapa
Feb 24, 2009·Medical Hypotheses·Mark F McCartyFrancisco Contreras

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Citations

Dec 4, 2012·The Journal of Clinical Investigation·Mahadeo A SukhaiAaron D Schimmer
Aug 19, 2014·Trends in Parasitology·Satoshi Omura, Andy Crump
Dec 25, 2015·Proceedings of the National Academy of Sciences of the United States of America·Miki NishioAkira Suzuki
Sep 11, 2012·Journal of Applied Toxicology : JAT·Gabriela MolinariMarcelo L Larramendy
Jul 1, 2015·Brain : a Journal of Neurology·Jinlong YinJong Heon Kim
Aug 16, 2016·Veterinary Parasitology·Shoaib Ashraf, Roger Prichard
Jul 20, 2016·Cancers·Kamal AhmedVladimir L Katanaev
Jun 9, 2011·ACS Medicinal Chemistry Letters·Sonali B Fonseca, Shana O Kelley
Feb 23, 2018·Antimicrobial Resistance and Infection Control·Shoaib AshrafXin Zhao
Feb 20, 2020·Cancers·Anna V WojcickiKathleen M Sakamoto
Jun 21, 2020·Journal of Clinical Medicine·Debora ValliMyriam Alcalay
Dec 20, 2017·Molecular Medicine Reports·Guadalupe Dominguez-GomezAlfonso Dueñas-González
Jun 28, 2020·Blood Cancer Journal·Caterina MezzatestaBeat C Bornhauser
Jun 20, 2019·Journal of Experimental & Clinical Cancer Research : CR·Lu JiangYi-Jun Wu
Apr 3, 2020·Journal of Cellular and Molecular Medicine·Liang ChenSongqiang Xie
Apr 1, 2019·Cancer Reports·Travis NemkovJulie A Reisz
Oct 9, 2020·Journal of Experimental & Clinical Cancer Research : CR·Faiqa MudassarEric Hau
Jan 25, 2021·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Xiaodi ZhuRonglan Zhao
Nov 16, 2019·European Journal of Pharmacology·Michał AntoszczakAdam Huczyński
Sep 25, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Mingyang TangQiang Fang
Oct 24, 2020·International Journal of Molecular Sciences·Mariana NunesSara Ricardo
Jul 3, 2019·Current Medicinal Chemistry·Sandra Cortez-MayaGildardo Rivera
Apr 1, 2021·Bulletin of Experimental Biology and Medicine·J V BukanovaV G Skrebitsky
Apr 21, 2021·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Rodrigo Romero-NavaJulio C Almanza-Pérez
May 25, 2021·International Journal for Parasitology. Drugs and Drug Resistance·Sandra NoackPaul M Selzer

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