HGF-mimic antibody administration to counteract doxorubicin cardiotoxicity

Objective: Doxorubicin (Doxo) is a highly effective and widely used anti-cancer drug. Unfortunately, its use is limited by its cumulative dose-dependent cardiotoxicity {CTX). Various molecular mechanisms are involved in Doxo-mediated CTX, including DNA damage, oxidative stress, apoptosis and dysregulation of autophagy in cardiomyocytes. The addition of cardioprotectants to chemotherapy has been proposed as a preventing strategy to reduce the CTX risk. Thus, new agents targeting the detrimental activities of Doxo are attractive candidates as cardioprotective molecules. The Hepatocyte Growth Factor (HGF)/Met receptor couple has been shown to protect from cell death, oxidative stress and excessive autophagy in cardiac cells. In a previous work, we have demonstrated that agonist anti-Met antibodies, that mimic the biological effects of HGF, mitigate the cardiac damage derived from hypoxia. In this work, we exploited the potential cardioprotective function of an HGF-mimic antibody in the context of Doxo-CTX. Methods: Adult male C57BL/6J mice were randomized to placebo (group 1), Doxo (group 2) and Doxo+ the HGF-mimic antibody (group 3). Mice were treated with i.p. injections of PBS (group 1) or Doxo 7 mg/kg (group 2 and 3) for 3 weeks. Group 3 received the agonist antibody (5 mg/kg) the day before each cycle of chemotherapy. Body weight was measured weekly. The cardiac function was assessed by magnetic resonance imaging (MRI) at week 5 and 6 (2 and 3 weeks after cessation of chemotherapy). At sacrifice, the mice organs were weighted and the heart was examined through histological and molecular analysis. Results: The treatment with the HGF-mimic antibody prevents the Doxo-induced cardiomyopathy in mice. In particular. MRI analysis showed that Met agonist antibody administration improves the heart systolic function through a thickening of contractile fibers, indicated by both MRI and heart weight measurement. In addition, Met receptor agonist antibody reduced the death rate and the loss of body weight and muscle volume produced by Doxo. From a molecular point of view, the presence of HGF-mimic antibody attenuated Doxo-mediated cell death mechanisms: apoptosis, excessive autophagy and mitochondrial dysfunction. In addition, the presence of antibody modulated DNA repair in response to DNA damage. Conclusions: Altogether, these results suggest that the HGF-mimic antibody prevents some of the cardiotoxic effects mediated by Doxo. Thus. HGF-mimic can be proposed as no