Metabonomic identification of novel biomarkers in doxorubicin cardiotoxicity and protective effect of the natural antioxidant oleuropein

Abstract

Doxorubicin (DXR) is a commonly used antineoplastic agent; however, its use is limited due to cardiotoxicity. Oxidative stress and consequent alterations of cardiac energetics are involved in the development of DXR toxicity. Oleuropein (Oleu) is a phenolic antioxidant, present in olive tree, reported to confer protection against DXR cardiotoxicity. In this study, NMR based-metabonomics was applied to characterize the metabolic profile of the acute DXR cardiotoxicity in rats and to evaluate the metabolic alterations conferred by co-treatment with Oleu. Wistar rats were divided into six groups and treated as follows: control group with a single injection of 2 mL normal saline intraperitoneally (i.p.), DXR group with a single dose of 20 mg/kg, i.p and DXR plus Oleu groups with 20mg/kg DXR i.p., and 100 or 200 mg/kg/BW of Oleu i.p. for 5 or 3 consecutive days starting either 2 days before or on the day of DXR administration. Hearts were excised 72 h after DXR treatment and (1)H-NMR spectra of aqueous myocardium extracts were recorded. Principal Component Analysis (PCA) and Partial Least Square Discriminant Analysis (PLS-DA) revealed differences in the metabolic profile between control and DXR attributed to several metabolites. A number of them were quantified by integration of the NMR spectra. Myocardial levels of acetate and succinate were increased in DXR compared to controls, while branched amino acids were decreased. These results correlate with nonenzymatic conversion of pyruvate to acetate and of alpha-ketoglutarate to succinate by DXR free radicals. Oleu completely restored the changes of metabolites to the normal levels. Acetate and succinate constitute novel biomarkers related to DXR, and Oleu treatment aids the compensation of distressed energy metabolic pathways.

Gas chromatography time-of-flight mass spectrometry based metabolomic approach to evaluating toxicity of triptolide

“…Because low-molecular-weight compounds are the endpoints of metabolism and systemic functions, their in vivo levels reflect the physiological and biochemical status of the organism. Thus, their measurement has the potential to evaluate the toxicity, identify the toxic markers or organ-specific markers, and explore the metabolism-related mechanism (Nicholson et al 2002;Robertson 2005;Keun 2006; Schnackenberg and Beger 2008;Griffin and Bollard 2004;Beger et al 2010;Andreadou et al 2009;Clarke and Haselden 2008;Collings and Vaidya 2008;Hines et al 2010;Goodsaid et al 2009;Boudonck et al 2009). Although dozens of metabolomcis/ metabonomics studies have been conducted to explore toxicity and achieved fruitful results (reviewed by Beger et al 2010;Schnackenberg and Beger 2008;Robertson 2005;Keun 2006; Griffin and Bollard 2004;Collings and Vaidya 2008;Ebbels et al 2007;Clarke and Haselden 2008;Nicholson et al 2002), few of them have associated the routine toxicity data with those from metabolomics studies both in qualitative and quantitative ways.…”

Metabolomics in Cardiovascular Disease: Towards Clinical Application

“…So far, reports regarding heart disease and drug treatments in the literature are focused on animal models either studying drug toxicity [Perrine et al, 2009, Andreadou et al, 2009 or the effect of antioxidant intervention [Constantinou et al, 2009]. This relative lack of reports may be due to the fact that the number of new drugs under development in the cardiovascular area is not as high as in other fields such as oncology.…”

Metabolomics — A wide-open door to personalized treatment in chronic heart failure?

“…lipids, sugars, organic acids, amino acids) reflecting the complete metabolic phenotype. This -omics technique has already been used for identification of markers associated with various pathologies such as myocardial ischemia [4][5][6], cardiogenic shock [7], atherosclerosis or future cardiovascular events [8][9][10], diabetes mellitus [11], atrial fibrillation [12,13] and chemotherapy-induced cardiotoxicity [14]. The number of studies on application of metabolomics in heart failure assessment is rapidly growing, however the heterogeneity in methodology (e.g.…”