Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: Mechanisms and implications

Abstract

Doxorubicin (DOX) is one of the most powerful and widely prescribed chemotherapeutic agents to treat divergent human cancers. However, the clinical use of DOX is restricted due to its severe cardiotoxic side-effects. There has been ongoing search for cardioprotectants against DOX toxicity. Inorganic nitrate has emerged as a bioactive compound that can be reduced into nitrite and nitric oxide in vivo and in turn plays a therapeutic role in diseases associated with nitric oxide insufficiency or dysregulation. In this review, we describe a novel concept of using dietary supplementation of inorganic nitrate to reduce DOX-induced cardiac cellular damage and dysfunction, based on our recent promising studies in a mouse model of DOX cardiotoxicity. Our data show that chronic oral ingestion of sodium nitrate, at a dose equivalent to ~400% of the Acceptable Daily Intake of the World Health Organization, alleviated DOX-induced left ventricular dysfunction and mitochondrial respiratory chain damage. Such cardioprotective effects were associated with reduction of cardiomyocyte necrosis/apoptosis, tissue lipid peroxidation, and mitochondrial H2O2 generation following DOX treatment. Furthermore, proteomic studies revealed enhanced cardiac expression of mitochondrial antioxidant enzyme – peroxiredoxin 5 in the nitrate-treated animals. These studies suggest that inorganic nitrate could be an inexpensive therapeutic agent for long-term oral administration in preventing DOX-induced cardiac toxicity and myopathy during the prolonged pathological process. Future clinical trials in the cancer patients undergoing DOX chemotherapy are warranted to translate these experimental findings into an effective new therapy in preventing the DOX-induced cardiomyopathy.

Peroxisome Proliferator-Activated Receptor-α Inhibition Protects Against Doxorubicin-Induced Cardiotoxicity in Mice

“…Cardiotoxicity is the overriding drawback by which most patients fail to survive even long after the cessation of the drug, leading to degenerative cardiomyopathy and heart failure [2,3]. Doxorubicin-induced cardiotoxicity occurs in two forms: acute and chronic, which occurs in 11 and 1.7 % of cases, respectively [4].…”

Beetroot juice reduces infarct size and improves cardiac function following ischemia–reperfusion injury: Possible involvement of endogenous H2S

“…12 In addition, we recently demonstrated that oral nitrate supplementation protects against doxorubicin-induced cardiomyopathy by improving mitochondrial function. 13,14 Beetroot juice (BRJ) is one of the highest nitratecontaining vegetable products. The consumption of BRJ exerts beneficial effects in healthy volunteers, including lowering of both systolic and diastolic blood pressures, through elevation of cyclic guanosine monophosphate (cGMP) concentration, and protection of the endothelium from I/R-induced endothelial damage.…”

“…Supplemental nitrate in the drinking water for seven days increased blood and tissue NO products and significantly reduced infarct size. 10 We recently demonstrated that nitrate supplementation also attenuated cardiotoxicity of doxorubicin -a highly effective anticancer drug 13,14 and the protective effects of nitrate were associated with increase of plasma nitrate-nitrite levels 13 and upregulation of cardiac Prx5. 24 Contrary to our expectation, the present results indicated that the BJR-induced cardioprotection was not associated with significant restoration of plasma concentrations of nitrate and NO x , which were significantly suppressed at the end of I/R ( Figure 5).…”

Current views on anthracycline cardiotoxicity

“…Top IIb is present in quiescent cells such as cardiomyocytes, and its inhibition by anthracyclines causes DNA double-strand breaks and transcriptome changes (responsible for defective mitochondrial biogenesis) and ROS formation [7]. Knowledge of the molecular mechanisms of anthracycline CTX is fundamental for understanding and selecting pharmacological [8] and non-pharmacological [9,10] strategies for CTX treatment and prevention.…”

“…Based on preclinical evidence, use of oral nitrate supplementation could be a novel preventive approach for effectively reducing CTX in cancer patients receiving anthracyclines [10]. Also, aerobic exercise is a promising strategy to prevent anthracycline-induced cardiac injury [9,97].…”