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.