Research article
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Anti-erbB2 treatment induces cardiotoxicity by interfering with cell survival pathways
Thea Pugatsch , Suzan Abedat , Chaim Lotan and Ronen Beeri
The Cardiovascular Research Center, Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Breast Cancer Research 2006, 8:R35 doi:10.1186/bcr1523
The electronic version of this article is the complete one and can be found online at:
http://breast-cancer-research.com/content/8/4/R35
Received 22 March 2006
Revisions requested 12 June 2006
Revisions received 26 June 2006
Accepted 26 June 2006
Published 13 July 2006
© 2006 Pugatsch et al.; licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (
http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Outline Abstract
Abstract
Introduction
Materials and methods
Results
Discussion
Conclusion
Abbreviations
Competing interests
Authors' contributions
Acknowledgements
References
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
Outline Introduction
Abstract
Introduction
Materials and methods
Results
Discussion
Conclusion
Abbreviations
Competing interests
Authors' contributions
Acknowledgements
References
Human epidermal growth factor receptor (Her)-2 (ErbB-2), a 185 kDa transmembrane glycoprotein receptor with intrinsic tyrosine kinase activity, is thought to be one of the important mediators of cell growth [1-5]. It is overexpressed in 25–30% of human breast cancers, plays a role in its pathogenesis and is a predictive marker for poor prognosis in patients with metastatic disease [6-10].
Over recent years new therapies were developed to target tumour cells with Her-2 overexpression by blocking Her-2 on the cell surface of the tumour cells, thereby inhibiting their growth. The most widely used drug based on this principle is Trastuzumab (Herceptin®, Genentech Inc., San Francisco, CA, USA), a high-affinity humanized anti-Her-2 antibody that was shown to benefit patients with Her-2-overexpressing breast cancer, either as a single agent or in combination with chemotherapy [6,11,12]. In women who had received at least one prior chemotherapeutic regimen for metastatic disease, the response rate was found to be 15% and in previously untreated patients 23%.
One of the major side effects noted was cardiotoxicity [6]. Congestive heart failure linked to Herceptin therapy may be severe and has been associated with disabling symptoms. Of patients receiving Herceptin together with paclitaxel, 12% developed cardiac dysfunction, as compared with 1% receiving paclitaxel alone; the number increased further when Herceptin was administered in combination with anthracyclines (27%) compared with anthracyclines alone (7%) [6,13]. No data are yet available on identification of patients who are at risk for developing cardiac dysfunction when they receive anti-erbB2 therapy, although both prior cardiotoxic therapy (e.g. radiation to the breast area) and advanced age may play a role.
ErbB-2 forms heterodimers with other ErbB receptors (ErbB-3/ErbB-4) that can bind neuregulins, polypeptide growth factors that are known to promote survival and growth of cardiac myocytes [14,15]. Thus, blocking ErbB-2 with a monoclonal antibody may inhibit the myocardial adaptation to physiological stress and injury, such as that resulting from chemoradiotherapy, ultimately leading to cardiac failure in susceptible patients.
In order to elucidate the molecular mechanisms that lead to cardiotoxocity, we studied the effect of the rat-anti-erbB2 monoclonal antibody B-10 on spontaneously beating primary cultures derived from rat neonatal hearts. B-10 has previously been shown to have activity biologically similar to that of the humanized antibody that is used in the clinical setting [16].
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