Molecular and cellular mechanisms of anthracycline cardiotoxicity
- 995 Downloads
The molecular and cellular mechanisms that cause cumulative dose-dependent anthracycline-cardiotoxicity remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes in vitro have demonstrated several forms of cellular injury. Cell death in response to anthracyclines can be observed by one of several mechanisms including apoptosis and necrosis. Cell death by apoptosis can be inhibited by dexrazoxane, the iron chelator that is known to prevent clinical development of heart failure at high cumulative anthracycline exposure. Together with clinical evidence for myocyte death after anthracycline exposure, in the form of elevations in serum troponin, make myocyte cell death a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular ‘sarcopenia’ characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. Titin is an entropic spring element in the sarcomere that regulates length-dependent calcium sensitivity. Thus titin degradation may lead to impaired diastolic as well as systolic dysfunction, as well as potentiate the effect of suppression of transcription of sarcomere proteins. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. Studies of erbB2 function in viro suggest that signaling through erbB2 by the growth factor neuregulin may regulate cardiac myocyte sarcomere turnover, as well as myocyte-myocyte/myocyte-matrix force coupling. A combination of further in vitro studies, with more careful monitoring of cardiac function after exposure to these cancer therapies, may help to understand to what extent these mechanisms are at work during clinical exposure of the heart to these important pharmaceuticals.
KeywordsAnthracyclines Myocyte Neuregulin Sarcomere Titin Sarcopenia
This work was supported by the American Heart Association.
- 15.Sheng, Z., Knowlton, K., Chen, J., Hoshijima, M., Brown, J. H., & Chien, K. R. (1997). Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. The Journal of Biological Chemistry, 272, 5783–5791.PubMedCrossRefGoogle Scholar
- 29.Grillot, D., Gonzalez-Garcia, M., Ekhterae, D., Duan, L., Inohara, N., Ohta, S., Seldin, M., & Nunez, G. (1997). Genomic organization, promoter analysis and chromsome localization of the mouse bcl-x gene. Journal of Immunology, 158, 4750–4757.Google Scholar
- 30.O’Prey, J., Ramsay, S., Chambers, I., & Harrison, P. R. (1993). Trascriptional up-regulation of the mouse cytosolic glutathione peroxidase gene in erythroid cells is due to a tissue-specific 3′ enhancer containing functionally important CACC/GT motifs and binding sites for GATA and Ets trancription factors. Molecular andl Cellular Biology, 13, 6290–6303.Google Scholar
- 39.Von Hoff, D., Rozencweig, M., & Piccart, M. (1982). The cardiotoxicity of anti-cancer agents. Seminars on Oncology, 9, 23–33.Google Scholar
- 52.Baselga, J. (2000). Current and planned clinical trials with trastuzumab (Herceptin). Seminars on Oncology, 27(5 Suppl 9), 27–32.Google Scholar
- 55.Chien, K. R. (2000). Myocyte survival pathways and cardiomyopathy: Implications for trastuzumab cardiotoxicity. Seminars on Oncology, 27(6 Suppl 11), 9–14; discussion 92–100.Google Scholar