Abstract 9375: Melatonin and Metformin Exert Cardioprotection Against Trastuzumab-induced Cardiotoxicity Through Modulating Cardiac Mitochondrial Dynamics in Rats

Introduction: The combination of doxorubicin (Dox) and trastuzumab (Trz) in patients with metastatic human epidermal growth factor receptor 2 (HER2) positive tumors is limited by cardiotoxicity, as manifested by cardiac dysfunction. Although several pharmacological interventions including melatonin and metformin have been shown cardioprotection in several cardiovascular diseases, their roles in Trz-induced cardiotoxicity and the underlying mechanisms have never been tested. Hypothesis: We hypothesized that either melatonin or metformin exerts cardioprotection against Trz-induced cardiac injury through attenuating cardiac mitochondrial dysfunction. Methods: Twenty male Wistar rats were randomly divided into control group (n=5) and Trz group (n=15). Trz-treated rats were intraperitoneally injected with 4 mg/kg/day of Trz for 7 consecutive days, while control rats were injected with normal saline. Then, Trz-treated rats were equally subdivided into 3 co-treatment groups to receive normal saline, melatonin (10 mg/kg/day), or metformin (250 mg/kg/day) via oral gavage. Left ventricular (LV) function was performed using echocardiography, and the hearts were rapidly removed to determine cardiac mitochondrial function and mitochondrial dynamic proteins. Results: Trz induced excessive mitochondrial oxidative stress and mitochondrial dynamics imbalance, eventually leading to LV dysfunction (Fig. 1A-D). Treatment with either melatonin or metformin similarly improved contractile function (Fig. 1A), reduced mitochondrial ROS production (Fig. 1B) and mitochondrial dynamic index (Drp1/Mfn2) (Fig. 1C & D), resulting in improved LV function. Conclusions: Melatonin and metformin equally exerted cardioprotection against Trz-induced cardiotoxicity. Our findings suggested that either melatonin or metformin can be used as a concomitant intervention for cardioprotection in patients with metastatic HER2 positive tumors being treated with Trz.