Role of aldehydes metabolism in the doxorubicin-induced cardiomyopathy: preventive and therapeutic effects of Alda-1

• Grant number: 18/14491-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2018
• End date: September 30, 2021
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Patricia Chakur Brum
• Grantee: Thiago Nunes de Menezes
• Host Institution: Escola de Educação Física e Esporte (EEFE). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 15/22814-5 - Cancer and heart: new paradigms of diagnosis and treatment, AP.TEM

Abstract

Doxorubicin, an antibiotic with high efficacy in cancer treatment, has its therapeutic use often limited by the fact that it may induce cardiotoxicity. This drug can increase the chance of one's developing cardiomyopathy or even heart failure by up to 20%, with the pathophysiological mechanisms involved still being controversial. The establishment of cardiac damage induced by doxorubicin may occur by its negative interference in mitochondrial metabolism, resulting in free radical accumulation and consequent production of highly reactive and cardiotoxic aldehydes. To date there are no therapies capable of nullifying or minimizing the cardiotoxic effects of doxorubicin. Therefore, the discovery of therapeutic alternatives capable of blocking doxorubicin-induced cardiac metabolic dysfunction is of utmost importance. The selective activation of the mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2), which is responsible for removing cardiotoxic aldehydes, is able to reduce cardiac aldehyde stress, restoring mitochondrial metabolism, minimizing oxidative stress and improving cardiac function in rats with heart failure. Considering the absence of effective pharmacological strategies against the aforementioned problem, our proposal is to evaluate the therapeutic potential of sustained pharmacological activation of ALDH2 (using Alda-1) in the prevention and treatment of doxorubicin-induced cardiotoxicity. The results obtained could open a new perspective in the development of tools to abolish or minimize the deleterious effects of doxorubicin on the heart.