Sulforaphane protects the heart from doxorubicin-induced toxicity

Cardiotoxicity is one of the major side effects encountered during cancer chemotherapy with doxorubicin (DOX) and other anthracyclines. Previous studies have shown that oxidative stress caused by DOX is one of the primary mechanisms for its toxic effects on the heart. Since the redox-sensitive transcription factor, Nrf2, plays a major role in protecting cells from the toxic metabolites generated during oxidative stress, we examined the effects of the phytochemical sulforaphane (SFN), a potent Nrf2-activating agent, on DOX-induced cardiotoxicity. These studies were carried out both in vitro and in vivo using rat H9c2 cardiomyoblast cells and wild type 129/sv mice, and involved SEN pretreatment followed by SFN administration during DOX exposure. SEN treatment protected H9c2 cells from DOX cytotoxicity and also resulted in restored cardiac function and a significant reduction in DOX-induced cardiomyopathy and mortality in mice. Specificity of SFN induction of Nr12 and protection of H9c2 cells was demonstrated in NEU knockdown experiments. Cardiac accumulation of 4-hydroxynonenal (4-HNE) protein adducts, clue to lipid peroxidation following DOX-induced oxidative stress, was significantly attenuated by SEN treatment. The respiratory function of cardiac mitochondria isolated from mice exposed to DOX alone was repressed, while SEN treatment with DOX significantly elevated mitochondrial respiratory complex activities. Co-administration of SFN reversed the DOX-associated reduction in nuclear Nr12 binding activity and restored cardiac expression of Na2-regulated genes at both the RNA and protein levels. Together, our results demonstrate for the first time that the Nr12 inducer, SFN, has the potential to provide protection against DOX-mediated cardiotoxicity. Published by Elsevier Inc.