Abstract 15445: Combination Therapy With Pde5-mtor Inhibitors Attenuates Cardiotoxicity While Enhancing Cancer Cell Death Following Treatment With Doxorubicin and Human Epidermal Growth Factor Receptor 2 Inhibitor

Abstract

Backgound: Chemoimmunotherapy with Doxorubicin (DOX) and Trastuzumab (Trast, a monoclonal antibody against human epidermal growth factor receptor 2, ERBB2) has synergistic effects with immense improvement in disease-free survival in breast cancer patients. However, because of the high incidence of heart failure, the concomitant treatment with DOX and trastuzumab has been restricted. In the present study, we examined whether a novel combination therapy with the phosphodiesterase 5 (PDE5) inhibitor (sildenafil, Sild) and mTOR inhibitor (rapamycin, Rapa) can attenuate cardiotoxicity-induced by DOX+Trast. Methods & Results: Human ventricular cardiomyocytes (AC16) and ErbB2 + breast cancer cells (SKBr3) were treated with DOX (1μM), AG-825 (ERBB2 inhibitor, 5μM) and/or Sild (10μM) and Rapa (100 nM) for 24 hours. AC16 cell death was significantly higher with DOX+AG825 as compared to the single drug treatment, which was significantly reduced with Sild+Rapa treatment (Fig. A ). Contrarily, the enhanced SKBr3 cell death with DOX+AG825 treatment was further increased by Sild+Rapa treatment (Fig. B ). To evaluate therapeutic effect of Sild+Rapa against cardiotoxicity, C57BL/6J mice were treated for 2 weeks with DOX (6 mg/kg/twice/week, i.p.). After 1week interval, mice were treated with Trast for 2 weeks (2.5 mg/kg/twice/week, i.p.) (Fig. C ). Rapa (0.25 mg/kg/twice/week, i.p.) and Sild (0.4 mg/ml in drinking water) were administered for 12 weeks. Body weight, left ventricular ejection fraction (LVEF) and E/A ratio as well as survival were significantly decreased in mice with the sequential treatment of DOX and Trast as compared to DOX alone (Fig. D-G ). Treatment with Sild+Rapa significantly improved body weight and survival with restoration of cardiac function in mice treated with DOX±Trast. Conclusion: Combination treatment with Sild and Rapa could be a novel strategy to attenuate cardiotoxicity associated with DOX±Trast and improvement of cancer chemotherapy.