title: High Throughput Screening Identifies a Novel Compound Protecting Cardiomyocytes from Doxorubicin-Induced Damage.
abstract: Antracyclines are effective antitumor agents. One of the most commonly used antracyclines is doxorubicin, which can be successfully used to treat a diverse spectrum of tumors. Application of these drugs is limited by their cardiotoxic effect, which is determined by a lifetime cumulative dose. We set out to identify by high throughput screening cardioprotective compounds protecting cardiomyocytes from doxorubicin-induced injury. Ten thousand compounds of ChemBridge's DIVERSet compound library were screened to identify compounds that can protect H9C2 rat cardiomyocytes against doxorubicin-induced cell death. The most effective compound proved protective in doxorubicin-treated primary rat cardiomyocytes and was further characterized to demonstrate that it significantly decreased doxorubicin-induced apoptotic and necrotic cell death and inhibited doxorubicin-induced activation of JNK MAP kinase without having considerable radical scavenging effect or interfering with the antitumor effect of doxorubicin. In fact the compound identified as 3-[2-(4-ethylphenyl)-2-oxoethyl]-1,2-dimethyl-1H-3,1-benzimidazol-3-ium bromide was toxic to all tumor cell lines tested even without doxorubicine treatment. This benzimidazole compound may lead, through further optimalization, to the development of a drug candidate protecting the heart from doxorubicin-induced injury.
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary ; Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Gergely
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
authors.forename: Csaba
authors.initials: C
authors.lastname: Hegedűs
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary.
authors.forename: Petra
authors.initials: P
authors.lastname: Lakatos
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary ; MTA-DE Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, Debrecen 4032, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Kovács
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged 6720, Hungary.
authors.forename: Renáta
authors.initials: R
authors.lastname: Gáspár
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Szeged, Szeged 6720, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Csont
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Debrecen 4032, Hungary ; MTA-DE Cell Biology and Signaling Research Group of the Hungarian Academy of Sciences, Debrecen 4032, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Virág
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004317:Doxorubicin / Q000494:pharmacology*; D057166:High-Throughput Screening Assays; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C000606672:3-(2-(4-ethylphenyl)-2-oxoethyl)-1,2-dimethyl-1H-3,1-benzimidazol-3-ium; D000903:Antibiotics, Antineoplastic; D001562:Benzimidazoles; D020011:Protective Agents; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases