3,3'-Diindolymethane ameliorates adriamycin-induced cardiac fibrosis via activation of a BRCA1-dependent anti-oxidant pathway

Abstract

The cardiotoxicity of adriamycin greatly limits its application in the treatment of cancer. Heart failure that is caused by adriamycin-treatment induced cardiac fibrosis is a major cause of death in patients who are treated with this medication. The severe oxidative stress that is induced by adriamycin is considered to be one of the primary mechanisms by which fibrogenesis of cardiac tissue occurs. In the present study, we demonstrate that 3,3'-diindolymethane (DIM) exhibits a significant anti-fibrosis effect on cardiac tissue in an animal model of adriamycin-induced cardiac fibrosis (AICF). Further studies demonstrated that DIM is able to dramatically up-regulate the expression of breast cancer type 1 susceptibility protein (BRCA1) in cardiac tissue and fibroblast, which subsequently activate the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The upregulation of this transcription factor resulted in the expression of several anti-oxidant genes in the cell. Because DIM is a safe food additive that has been used for decades, our findings suggest that there is a great potential for this chemical to be developed into a clinical medication for the treatment of adriamycin-induced heart failure during cancer therapy.