title: BGP-15, a PARP-inhibitor, prevents imatinib-induced cardiotoxicity by activating Akt and suppressing JNK and p38 MAP kinases.
abstract: In this study, we investigate the cardiotoxic effects of the well-known cytostatic agent imatinib mesylate (Gleevec), and presented evidence for the cardioprotective effect of BGP-15 which is a novel insulin sensitizer. The cardiotoxic effect of imatinib mesylate was assessed in Langendorff rat heart perfusion system. The cardiac high-energy phosphate levels (creatine phosphate (PCr) and ATP) were monitored in situ by (31)P NMR spectroscopy. The protein oxidation, lipid peroxidation, and the activation of signaling pathways were determined from the freeze-clamped hearts. Prolonged treatment of the heart with imatinib mesylate (20 mg/kg) resulted in cardiotoxicity, which were characterized by the depletion of high-energy phosphates (PCr and ATP), and significantly increased protein oxidation and lipid peroxidation. Imatinib mesylate treatment-induced activation of MAP kinases (including ERK1/2, p38, and JNK) and the phosphorylation of Akt and GSK-3beta. BGP-15 (200 μM) prevented the imatinib mesylate-induced oxidative damages, attenuated the depletion of high-energy phosphates, altered the signaling effect of imatinib mesylate by preventing p38 MAP kinase and JNK activation, and induced the phosphorylation of Akt and GSK-3beta. The suppressive effect of BGP-15 on p38 and JNK activation could be significant because these kinases contribute to the cell death and inflammation in the isolated perfused heart.
authors.affiliation: Department of Cardiology, Heart Institute, University of Pecs, Medical School, Ifjusag 13, Pecs 7624, Hungary. sarszegizsolt@gmail.hu
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Sarszegi
authors.forename: Eszter
authors.initials: E
authors.lastname: Bognar
authors.forename: Balazs
authors.initials: B
authors.lastname: Gaszner
authors.forename: Attila
authors.initials: A
authors.lastname: Kónyi
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Berente
mesh_terms: D000255:Adenosine Triphosphate; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001549:Benzamides; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006321:Heart / Q000187:drug effects; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010091:Oximes / Q000494:pharmacology*; D010725:Phosphocreatine / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000633:toxicity*; D010880:Piperidines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D002316:Cardiotonic Agents; D010091:Oximes; D010879:Piperazines; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011743:Pyrimidines; D010725:Phosphocreatine; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C405586:BGP 15