Targeting Inflammation, Oxidative Stress, and Apoptosis by Indole-3-Carbinol to Ameliorate Doxorubicin- Induced Cardiotoxicity in Mice

Abstract

Background: Doxorubicin (DOX) is an effective antineoplastic agent of the anthracycline group. However, as with most anticancer drugs, they cause some toxic effects, including major cardiotoxicity. Oxidative stress, inflammation and apoptosis contribute to the pathological basis of doxorubicin (DOX)-induced cardiotoxicity. Indole-3-carbinol is a cruciferous-derived phytochemical, with potential anti-inflammatory and antioxidant effects. Purpose: Our present study aimed to investigate the protective effects of I3C against DOX- induced cardiotoxicity in mice by Targeting Inflammation, Oxidative Stress, and Apoptosis. Methods: BALB/c mice were subjected to DOX (4 mg/kg/day, i.p.) once weekly on days 0, 7, 14, 21 (for 21 days) to generate DOX- induced cardiotoxicity. Indole-3-carbinol was administered daily orally in the diet at two dose levels; 1000 ppm and 2000 ppm for 7 days before and 42 days after first injection of DOX. Serum creatine kinase (CK-MB), lactate dehydrogenase (LDH) and troponin I (cTn-I) levels activities, which are cardiac function markers were determined. Also, the levels of malondialdehyde (MDA) was assessed and enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GPx) were assessed in the heart tissues to determine the protective effect of Indole-3-carbinol against oxidative stress. To determine the anti-inflammatory effect, the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) were assessed in the heart tissues. Parts of the heart were subjected to histopathological and immunohistochemical examinations. Results: Indole-3-carbinol in a dose‐dependent manner was found to have the ability to mitigate the harmful effects of DOX on myocardial muscles with significant decrease in serum levels of CK-MB, LDH and cTn-I. In addition, Indole-3-carbinol significantly inhibited DOX-induced cardiac oxidative stress as seen in the reduced level of MDA and increased SOD, CAT, GR and GPx cardiac tissue levels; Indole-3-carbinol significantly reduced inflammatory mediators TNF-α and IL-6 levels and inhibited cardiac apoptosis by modulating Caspase 3 cardiac tissue levels. Moreover, Indole-3-carbinol, in a dose‐dependent manner, had the ability to combat the histopathological and immunohistochemical changes induced by doxorubicin in cardiomyocytes. Conclusion: These results demonstrate that administration of I3C in a dose dependent manner prevents heart injury induced by DOX via its antioxidant, anti-inflammatory, and antiapoptotic activities.