Anti-erbB2 treatment induces cardiotoxicity by interfering with cell survival pathways

• Published in: Breast cancer research : BCR 2006-01, Vol.8 (4), p.R35-R35, Article R35
• Main Authors: Pugatsch, Thea, Abedat, Suzan, Lotan, Chaim, Beeri, Ronen
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Animals, Newborn; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - immunology; Apoptosis - drug effects; Calcium-binding proteins; Cell Survival - drug effects; Cells, Cultured; DNA microarrays; Epidermal growth factor; Gene Expression; Genetic transcription; Heart Diseases - immunology; Monoclonal antibodies; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Oligonucleotide Array Sequence Analysis; Rats; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - immunology; Tyrosine
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/bcr1523

Cardiac dysfunction is among the serious side effects of therapy with recombinant humanized anti-erbB2 monoclonal antibody. The antibody blocks ErbB-2, a receptor tyrosine kinase and co-receptor for other members of the ErbB and epidermal growth factor families, which is over-expressed on the surface of many malignant cells. ErbB-2 and its ligands neuregulin and ErbB-3/ErbB-4 are involved in survival and growth of cardiomyocytes in both postnatal and adult hearts, and therefore the drug may interrupt the correct functioning of the ErbB-2 pathway. The effect of the rat-anti-erbB2 monoclonal antibody B-10 was studied in spontaneously beating primary myocyte cultures from rat neonatal hearts. Gene expression was determined by RT-PCR (reverse transcription polymerase chain reaction) and by rat stress-specific microarray analysis, protein levels by Western blot, cell contractility by video motion analysis, calcium transients by the FURA fluorescent method, and apoptosis using the TUNEL (terminal uridine nick-end labelling) assay. B-10 treatment induces significant changes in expression of 24 out of 207 stress genes analyzed using the microarray technique. Protein levels of ErbB-2, ErbB-3, ErbB-4 and neuregulin decreased after 1 day. However, both transcription and protein levels of ErbB-4 and gp130 increased several fold. Calreticulin and calsequestrin were overexpressed after three days, inducing a decrease in calcium transients, thereby influencing cell contractility. Apoptosis was induced in 20% cells after 24 hours. Blocking ErbB-2 in cultured rat cardiomyocytes leads to changes that may influence the cell cycle and affects genes involved in heart functions. B-10 inhibits pro-survival pathways and reduces cellular contractility. Thus, it is conceivable that this process may impair the stress response of the heart.