Akt Rescue in Cardiomyocytes but not Breast Cancer Cells After Doxorubicin and Anti-erB2 Treatment

摘要

The proposed study will first evaluate the role of Akt, in protection against doxorubicin and anti-erbB2-cardiomyocyte toxicity, using adenoviral expression of active Akt, pharmacological inhibitors of this pathway, and two peptides that activate Akt, cardiotrophin-1 and urocortin. Since these peptides have not been reported expressed in breast tissues or cancer, to confirm this, we will evaluate the expression of both peptides and their receptors in six commonly studied breast cancer cell lines and 160 breast cancer tissue arrays by immunohistochemistry and western blotting methods. Even if expression is observed in breast tissue, peptide treatment may improve cancer therapy as seen in other models. In aim 3, the cardiotrophin-1 and urocortin cardiac protection strategy, will be tested against cardiac toxicity induced by doxorubicin, anti-erbB2, chemical inhibitors of erbB1 or erbB2, or combination treatments. This will be a direct comparison of rat and human cardiomyocytes with 6 breast cancer cell lines using MTT assay. Next both peptides, will be administered in pilot studies to Sprague Dawley rats to establish a dose that protects against doxorubicin induced cardiac toxicity. Finally, using a female nude rat breast cancer xenograph model, these peptides will be evaluated for specific cardiac protection, during treatment with doxorubicin, anti-erbB2, combination of doxorubicin and anti-erbB2 and controls. Echocardiography, to evaluate ejection fraction, white blood cell counts, to evaluate bone marrow toxicity, histopathology, xenograph tumor size and weights will be used to assess peptide cardiac specific protection and anti- neoplastic therapy. Relevance: Doxorubicin is currently a first choice drug for breast cancer treatment, limited in use by its cardiac toxicity. Combination drug treatment is the standard of care.