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

## TL;DR

Adding dietary nitrate and nitrite to doxorubicin treatment in mice with breast cancer protects the heart without reducing cancer-fighting effects.

## Contribution

Shows that nitrate and nitrite do not impair doxorubicin's anticancer efficacy in tumor-bearing mice.

## Key findings

- Nitrate and nitrite reduced cardiac fibrosis and oxidative protein damage in mice.
- Doxorubicin's antitumor efficacy was not compromised by nitrate and nitrite supplementation.
- No increase in pulmonary metastasis was observed with nitrate and nitrite treatment.

## Abstract

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 anticancer 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 four 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 antitumor 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 anticancer outcomes.

Chemotherapies such as doxorubicin can have toxic effects on healthy cardiovascular/heart tissue. Following up on a doxorubicin toxicity study in mice without tumors where nitrate water was cardioprotective (lessened toxicity), this study with tumor‐bearing mice undergoing doxorubicin treatment showed no negative effect of nitrate and nitrite on drug potency, no increase in metastasis to lung, but retention of cardioprotective effects.