Abstract 4639: Reproductive hormone levels modulate doxorubicin induced cardiomyopathy in female tumor-bearing spontaneously hypertensive rats

The anthracycline doxorubicin (dox) is known to cause cardiomyopathy, at least in part, through the generation of excess reactive oxygen species (ROS) in the mitochondria. Cardiomyocytes have higher concentrations of mitochondria and lower concentrations of antioxidants, making them more sensitive to excessive ROS. The incidence of dox induced cardiac stress is greater in pre-pubescent and post-menopausal females compared to age-matched males but lower in women of reproductive age. Previous studies have associated gender and age differences in cardiosensitivity with estrogen production. This is the first part of a two part study investigating the role that reproductive hormones (estrogen and progesterone) play in dox induced cardiotoxicity in female, tumor-bearing spontaneously hypertensive rats (SHRs). In this portion of the study our aim was to evaluate the effect of hormone therapy on cardioprotection from dox. Reproductively mature ovariectomized animals were implanted with time-release pellets containing a “carrier-matrix” (vehicle), 17-β-estradiol (E2), progesterone (P4), Tamoxifen (Tam) or combinations thereof. The animals were implanted with cells from an SHR-derived syngeneic breast cancer cell line (SST-2). Tumor-bearing animals were then treated with a single dose of saline or dox and monitored for 12 days. Daily vaginal cytologies were obtained to measure estrous cycle status. Serum was collected throughout the study to correlate estrous phase to E2 and P4 levels and evaluate serum protein cTnI as a biomarker for cardiac injury. In all hormone groups, dox exhibited significant anti-tumor activity and resulted in a net decrease in growth rate compared to saline controls. After 12 days exposure, animals treated with dox and implanted with Tam, Tam+E2 or vehicle pellets showed a significant increase in cTnI, indicative of cardiac damage. Dox treated animals with pellets containing E2, P4 or the combination showed a significant decrease in cTnI, demonstrating potential cardioprotection from reproductive hormone therapy. Furthermore, histopathology of cardiac sections from dox-treated groups displayed lower cardiomyopathy scores in animals that received E2, P4 or the combination of the two. We are currently evaluating additional endpoints for cardiotoxicity and cellular stress to assess the mechanism behind E2 and P4 cardioprotection from chemotherapy. Overall, our findings suggest that the hormones estrogen and progesterone reduce dox-induced cardiotoxicity. Citation Format: Kaytee L. Pokrzywinski, Elliot T. Rosen, Julia Bonanno, Thomas Biel, Delaram Moshkelani, Baikuntha Aryal, Steven Mog, V. Ashutosh Rao. Reproductive hormone levels modulate doxorubicin induced cardiomyopathy in female tumor-bearing spontaneously hypertensive rats. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4639.