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 H(2)O(2) 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.

• Authors: Lei Xi, Shu-Guang Zhu, Anindita Das, Qun Chen, David Durrant, Daniel C Hobbs, Edward J Lesnefsky, Rakesh C Kukreja
• Journal: Nitric oxide : biology and chemistry (Nitric Oxide) Vol. 26 Issue 4 Pg. 274-84 (May 15 2012) ISSN: 1089-8611 [Electronic] United States
• PMID: 22484629 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Review)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Antioxidants
• Cardiotonic Agents
• Cardiotoxins
• Nitrates
• Doxorubicin

Topics

• Animals
• Antibiotics, Antineoplastic (adverse effects, pharmacology)
• Antioxidants (pharmacology)
• Cardiotonic Agents (pharmacology)
• Cardiotoxins (adverse effects, pharmacology)
• Diet
• Doxorubicin (adverse effects, pharmacology)
• Drug Interactions
• Heart Diseases (chemically induced, prevention & control)
• Humans
• Nitrates (pharmacology)