Abstract 1611: Herceptin, an Antibody Against erbB2 Receptor, Induces Cardiomyocyte Death by Increasing Production of Reactive Oxygen Species
The tyrosine kinase receptor erbB2 (or Her2 in humans) is a member of the epidermal growth factor receptor. It is highly expressed in many cancer types, and its overexpression is correlated with a poor prognosis in breast and ovarian cancer. Treatment with Herceptin (a monoclonal antibody against the extracellular domain of Her2) has resulted in a significant improvement in survival of breast cancer patients overexpressing erbB2. However, this agent also causes cardiomyopathy and exacerbates anthracyclin-induced cardiotoxicity. Treatment of isolated cardiomyocytes with anti-erbB2 induces apoptosis through modulation of Bcl-xL and -xS. We hypothesized that the deleterious effects of Herceptin in cardiomyocytes are through an increase in the levels of reactive oxygen species (ROS). We first showed that erbB2 is expressed in neonatal rat cardiomyoctes (NRCM). We then measured the levels of ROS production by treating NRCM with 2, 7-dichlorodihydrofluorescein diacetate (DCF) followed by flow cytometry. Treatment of the cells with 0.1–1 μg of Herceptin resulted in a dose dependent increase in ROS production compared to IgG treated cell. Higher concentrations (5–10 μg) resulted in no significant increase in the levels of ROS. Our results suggest a role for ROS production in the deleterious effects of Herceptin on the heart in cancer patients. Thus, therapies targeting oxidative stress may have beneficial effects in this group of patients.