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Review
. 2012 May 15;26(4):274-84.
doi: 10.1016/j.niox.2012.03.006. Epub 2012 Apr 5.

Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: mechanisms and implications

Lei Xi  1 , Shu-Guang Zhu, Anindita Das, Qun Chen, David Durrant, Daniel C Hobbs, Edward J Lesnefsky, Rakesh C Kukreja
Affiliations
Review

Dietary inorganic nitrate alleviates doxorubicin cardiotoxicity: mechanisms and implications

Lei Xi et al. Nitric Oxide. .

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.

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Figures

Figure 1
Figure 1
Major pathways of cardiotoxicity of with doxorubicin and its metabolites. ROS – reactive oxygen species.
Figure 2
Figure 2
Distinctive pathways for the nitric oxide synthase (NOS) dependent and independent generation of nitric oxide (NO) in living organisms.
Figure 3
Figure 3
Effect of nitrate supplementation on doxorubicin (DOX)-induced left ventricular dysfunction. Nitrate intake restored the DOX-induced impairment in systolic pressure (A), end-diastolic pressure (B), positive, negative dP/dtmax (C, D), heart rate (E), and mean aortic blood pressure (F). Data are Mean±SEM (n=8 per group). * indicates P<0.05 versus all other groups; # indicates P<0.05 versus Control or Nitrate groups. Adopted from (14).
Figure 4
Figure 4
Assessment of plasma levels of nitrate (A), nitrite (B), and sum of nitrate and nitrite, i.e. NOx (C). Data are Mean±SEM (n=6 per group). * indicates P<0.05 versus all other groups; # indicates P<0.05 versus DOX group. Adopted from (14).
Figure 5
Figure 5
Effect of nitrate supplementation on DOX-induced tissue lipid peroxidation (A) and H2O2 generation from isolated mitochondria (B). Complex I substrate (glutamate + malate) and complex II substrate (succinate + rotenone) were utilized to identify the specific site(s) of H2O2 generation in the mitochondria. Data are Mean±SEM; n=6 per group for (A); n=5–8 per group for (B). * indicates P<0.05 versus all other groups; # indicates P<0.05 versus DOX group. Adopted from (14).
Figure 6
Figure 6
Graph A shows the representative magnified 2D-DIGE gel images focusing on protein spot #59, which was identified as peroxiredoxin 5 (Prx5) by MALDI TOF/TOF tandem mass spectrometry. Note the remarkable difference between DOX alone and Nitrate+DOX groups in the labeled fluorescent dye colors (top panel), spot density of the converted black-and-white images (bottom left), as well as the integrated 3 dimensional DeCyder software analysis output (bottom right) for this protein. Graph B [partially adopted from (15)] presents Western blots for Prx5 and α-Tubulin (loading control) in heart tissue and densitometric quantification of the α-Tubulin-normalized expression of Prx5 (Mean±SEM; n=4/group).
Figure 7
Figure 7
Effect of nitrate on the cancer-killing efficacy of DOX in vitro. The human prostate cancer cell line (DU145) were incubated with DOX (0.2 μmol/L) for 48 hours with or without co-incubation with 30, 60, or 90 μmol/L of nitrate in the cell culture medium. Cell proliferation was measured with a CellTiter 96 AQueous One Solution Cell Proliferation assay kit (Promega Corp.). Data are Mean±SEM (n=3 per group). * P<0.05 vs. Control; # P<0.05 vs. the corresponding dose of Nitrate group.
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References

    1. Bristow MR, Mason JW, Billingham ME, Daniels JR. Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med. 1978;88:168–175. - PubMed
    1. Singal PK, Iliskovic N. Doxorubicin-induced cardiomyopathy. N Engl J Med. 1998;339:900–905. - PubMed
    1. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin - A retrospective analysis of three trials. Cancer. 2003;97:2869–2879. - PubMed
    1. Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56:185–229. - PubMed
    1. Wallace KB. Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis. Cardiovasc Toxicol. 2007;7:101–107. - PubMed

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