title: 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.affiliation: VCU Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298-0204, United States. lxi@vcu.edu
authors.forename: Lei
authors.initials: L
authors.lastname: Xi
authors.forename: Shu-Guang
authors.initials: SG
authors.lastname: Zhu
authors.forename: Anindita
authors.initials: A
authors.lastname: Das
authors.forename: Qun
authors.initials: Q
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Durrant
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Hobbs
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lesnefsky
authors.forename: Rakesh C
authors.initials: RC
authors.lastname: Kukreja
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D054715:Cardiotoxins / Q000009:adverse effects / Q000494:pharmacology; D004032:Diet; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology*; D004347:Drug Interactions; D006331:Heart Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D006801:Humans; D009566:Nitrates / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D002316:Cardiotonic Agents; D054715:Cardiotoxins; D009566:Nitrates; D004317:Doxorubicin