Dietary nitrate and nitrite protect against doxorubicin-induced cardiac fibrosis and oxidative protein damage in tumor-bearing mice

Anthracycline-induced cardiotoxicity remains a major limitation in cancer therapy, affecting long-term cardiovascular health in survivors. Dietary nitrate supplementation has shown cardioprotective effects in preclinical models of doxorubicin (Dox)-induced and ischemia-reperfusion injury, but it is unclear whether nitrate and/or nitrite (NOx) would have adverse effects on the anti-cancer efficacy of the drug. To evaluate Dox efficacy against triple negative breast cancer (TNBC) in the presence of dietary nitrate and nitrite, tumor-bearing BALB/c mice (N=5 mice per group, 10 mice total) were treated with 4 weekly intravenous doses of Dox with or without NOx supplementation of their drinking water. Cardiac tissue from the NOx-treated mice exhibited less fibrosis and lower levels of 4-hydroxynonenal-modified proteins, a marker of lipid oxidation and oxidative stress. Tumor sizes varied, but most regressed by the final Dox dose. Importantly, NOx supplementation did not compromise the anti-tumor efficacy of Dox nor did it promote pulmonary metastasis; instead, a trend toward fewer metastatic lesions was observed. These findings support the potential clinical use of dietary nitrate and nitrite as adjuncts to Dox treatment to mitigate cardiotoxicity without impairing anti-cancer outcomes.