Inhibition of ErbB2/neuregulin signaling augments paclitaxel-induced cardiotoxicity in adult ventricular myocytes.
Paclitaxel (Taxol) has been successfully combined with the monoclonal antibody trastuzumab (Herceptin) in the treatment of ErbB2 overexpressing cancers. However, this combination therapy showed an unexpected synergistic increase in cardiac dysfunction. We have studied the mechanisms of paclitaxel/anti-ErbB2 cardiotoxicity in adult rat ventricular myocytes (ARVM). Myofibrillar organization was assessed by immunofluorescence microscopy and cell viability was tested by the TUNEL-, LDH- and MTT-assay. Oxidative stress was measured by DCF-fluorescence and myocyte contractile function by video edge-detection and fura-2 fluorescence. Treatment of ARVM with paclitaxel or antibodies to ErbB2 caused a significant increase in myofilament degradation, similarly as observed with an inhibitor of MAPK-signaling, but not apoptosis, necrosis or changes in mitochondrial activity. Paclitaxel-treatment and anti-ErbB2 reduced Erk1/2 phosphorylation. Paclitaxel increased diastolic calcium, shortened relaxation time and reduced fractional shortening in combination with anti-ErbB2. A minor increase in oxidative stress by paclitaxel or anti-ErbB2 was found. We conclude, that concomitant inhibition of ErbB2 receptors and paclitaxel treatment has an additive worsening effect on adult cardiomyocytes, mainly discernible in changes of myofibrillar structure and function, but in the absence of cell death. A potential mechanism is the modulation of the MAPK/Erk1/2 signaling by both drugs.
Pentassuglia
Laura
L
Swiss Cardiovascular Center Bern, University Hospital, CH-3010 Bern, Switzerland.
Timolati
Francesco
F
Seifriz
Franziska
F
Abudukadier
Kaisaier
K
Suter
Thomas M
TM
Zuppinger
Christian
C
D000818:Animals; D000911:Antibodies, Monoclonal / Q000633:toxicity*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002070:Butadienes / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology; D008297:Male; D008870:Microtubules / Q000187:drug effects; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D009210:Myofibrils / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology; D017239:Paclitaxel / Q000633:toxicity*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D002070:Butadienes; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D006023:Glycoproteins; D009570:Nitriles; D017239:Paclitaxel; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; C113580:U 0126; C483804:Erbb2 protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one