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Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: mechanisms and implications.
Nitric Oxide 2012; 26(4):274-84NO

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+Show Affiliations

VCU Pauley Heart Center, Division of Cardiology, Virginia Commonwealth University, Richmond, VA 23298-0204, United States. lxi@vcu.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

22484629

Citation

Xi, Lei, et al. "Dietary Inorganic Nitrate Alleviates Doxorubicin Cardiotoxicity: Mechanisms and Implications." Nitric Oxide : Biology and Chemistry, vol. 26, no. 4, 2012, pp. 274-84.
Xi L, Zhu SG, Das A, et al. Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: mechanisms and implications. Nitric Oxide. 2012;26(4):274-84.
Xi, L., Zhu, S. G., Das, A., Chen, Q., Durrant, D., Hobbs, D. C., ... Kukreja, R. C. (2012). Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: mechanisms and implications. Nitric Oxide : Biology and Chemistry, 26(4), pp. 274-84. doi:10.1016/j.niox.2012.03.006.
Xi L, et al. Dietary Inorganic Nitrate Alleviates Doxorubicin Cardiotoxicity: Mechanisms and Implications. Nitric Oxide. 2012 May 15;26(4):274-84. PubMed PMID: 22484629.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: mechanisms and implications. AU - Xi,Lei, AU - Zhu,Shu-Guang, AU - Das,Anindita, AU - Chen,Qun, AU - Durrant,David, AU - Hobbs,Daniel C, AU - Lesnefsky,Edward J, AU - Kukreja,Rakesh C, Y1 - 2012/04/05/ PY - 2011/09/13/received PY - 2012/02/11/revised PY - 2012/03/22/accepted PY - 2012/4/10/entrez PY - 2012/4/10/pubmed PY - 2012/12/14/medline SP - 274 EP - 84 JF - Nitric oxide : biology and chemistry JO - Nitric Oxide VL - 26 IS - 4 N2 - 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. SN - 1089-8611 UR - https://www.unboundmedicine.com/medline/citation/22484629/Dietary_inorganic_nitrate_alleviates_doxorubicin_cardiotoxicity:_mechanisms_and_implications_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1089-8603(12)00049-3 DB - PRIME DP - Unbound Medicine ER -