Protective Effects of Dexrazoxane against Doxorubicin-Induced Cardiotoxicity: A Metabolomic Study

<div><p>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.</p></div

Two-paired PLS-DA score plot and S-plot revealed DOX-induced metabolic perturbations.

<p>The comparative analysis of DOX_C and cancer control groups reveal altered metabolite levels following DOX treatment of tumor-bearing mice (<b>A</b>), while the comparative analysis of DOX_N and normal control groups reveal distinct metabolic effects of DOX in normal animals (<b>B</b>).</p

DZR protected against DOX-induced myocardial damage.

<p>Histopathology of HE staining of left ventricular walls indicated myocardial damage and cardioprotective effects of DZR(<b>A</b>). Magnification200x. DZR abrogated DOX-induced increase serum creatine kinase (<b>B</b>),CK-MB(<b>C</b>), cardiac LDH(D), cTNT(E), as well as decrease cardiac total glutathione (F) and GSH/GSSH ratio (G).</p

Overall profiling of the eight groups and abnormal metabolism in cancer.

<p>Score plot of the eight groups (A) shows treatment differences. The summary of pairwise metabolomics analysis of the model represents the cumulative R2X, R2Y and Q2 levels (<b>B</b>). The score plot and S-plot of the pairwise analysis of cancer and control groups reveal altered metabolites including creatine, UDP-glucose, VLDL/LDL, glycerol, TMAO, taurine, carnosine, lactate, acetone, glutamate, and aspartate (<b>C</b>).</p

Effect of DOX and DZR treatment on body and organ weights.

<p>Effect of DOX and DZR treatment on body and organ weights.</p

Cardioprotective effects of DZR on DOX-induced cardiotoxicity involving reprogrammed metabolic pathway.

<p>Cardioprotective effects of DZR on DOX-induced cardiotoxicity involving reprogrammed metabolic pathway.</p

Three paired PLS-DA score plot and S-plot reveal altered metabolites following combined therapy with DOX and DZR.

<p>The comparative analysis of DD_C and DD_N groups indicates metabolic regulation by DOX + DZR (<b>A</b>), The comparative analysis of DD_C and cancer control groups indicates the metabolic regulation by DOX + DZR in cancerous mice (<b>B</b>), and the comparative analysis of DD_N and normal control groups reveals the unique metabolic effect of DOX and DZR on normal animals.</p

The typical 1H-NMR spectra of the serum from the different treatment models.

<p>The metabolites are assigned and marked. The overlapping peaks were identified by adding a reference substance to the sample.</p

Flowchart outlining the study design and experimental process.

<p>Pairwise analysis was showed as the same color and broken line indicated the corresponding groups were not included in the pairwise analysis.</p

Two paired PLS-DA score and S-plot reveal altered metabolite levels following DZR treatment.

<p>The comparative analysis of DZR_C and cancer control groups revealed the altered metabolite levels resulting from DZR treatment of tumor-bearing mice (A), while the comparative analysis of DZR_N and normal control groups suggests distinct metabolic effect of DZR in normal animals.</p