Abstract
Cardioprotection of dexrazoxane (DZR) against doxorubicin (DOX)-induced cardiotoxicity is contentious and the indicator is controversial. A pairwise comparative metabolomics approach was used to delineate the potential metabolic processes in the present study. Ninety-six BALB/c mice were randomly divided into two supergroups: tumor and control groups. Each supergroup was divided into control, DOX, DZR, and DOX plus DZR treatment groups. DOX treatment resulted in a steady increase in 5-hydroxylysine, 2-hydroxybutyrate, 2-oxoglutarate, 3-hydroxybutyrate, and decrease in glucose, glutamate, cysteine, acetone, methionine, asparate, isoleucine, and glycylproline.DZR treatment led to increase in lactate, 3-hydroxybutyrate, glutamate, alanine, and decrease in glucose, trimethylamine N-oxide and carnosine levels. These metabolites represent potential biomarkers for early prediction of cardiotoxicity of DOX and the cardioprotective evaluation of DZR.
Highlights
Doxorubicin (DOX) is one of the most effective and widely used anticancer drugs
CT26 colorectal carcinoma cells were obtained from the Typical Culture Preservation Commission Cell Bank, Chinese Academy of Sciences (Shanghai, China).Creatine kinase (CK) and creatine kinase myocardial bound (CK-MB), lactate dehydrogenase (LDH) and toal glutathione / oxidized glutathione assay kits were purchased from Nanjing Jiancheng Bioengineering Institute (Jiangsu, China)
The mouse cardiac troponin T enzyme linked immunosorbent assay (ELISA) kits were from Sincere Biotech Co., Ltd (Beijing, China)
Summary
Doxorubicin (DOX) is one of the most effective and widely used anticancer drugs. Decreased dosage suggests reduced anticancer efficacy and poor survival. Curative doses often relate to severe cardiotoxicity, including life-threatening cardiomyopathy and congestive heart failure [2, 3]. The prevalence of DOX-induced heart failure was estimated at 5%, 26%, and 48% in patients at cumulative doses up to 400, 550, and 700 mg/m2, respectively[4]. Several potential mechanisms of DOX-induced cardiotoxicity were suggested, and after comprehensive basic and clinical investigation, the free radical hypothesis was acknowledged[5,6,7]. Dexrazoxane (DZR) mediates EDTA-like hydrolysis, resulting in chelating iron and decreased level of hydroxyl free radicals, and was clinically approved for protection against cardiotoxicity at cumulative doses of DOX up to 300 mg/m2
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