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

Fig 1. Flowchart outlining the study design and experimental process. Pairwise analysis was showed as the same color and broken line indicated the corresponding groups were not included in the pairwise analysis.

Fig 2. DZR protected against DOX-induced myocardial damage. Histopathology of HE staining of left ventricular walls indicated myocardial damage and cardioprotective effects of DZR(A). Magnification200x. DZR abrogated DOX-induced increase serum creatine kinase (B),CK-MB(C), cardiac LDH(D), cTNT(E), as well as decrease cardiac total glutathione (F) and GSH/GSSH ratio (G).

Fig 3. The typical 1H-NMR spectra of the serum from the different treatment models. The metabolites are assigned and marked. The overlapping peaks were identified by adding a reference substance to the sample.

Fig 4. Overall profiling of the eight groups and abnormal metabolism in cancer. 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). 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 (C).

Fig 5. Two-paired PLS-DA score plot and S-plot revealed DOX-induced metabolic perturbations. The comparative analysis of DOX_C and cancer control groups reveal altered metabolite levels following DOX treatment of tumor-bearing mice (A), while the comparative analysis of DOX_N and normal control groups reveal distinct metabolic effects of DOX in normal animals (B).

Fig 6. Two paired PLS-DA score and S-plot reveal altered metabolite levels following DZR treatment. 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.

Fig 7. Three paired PLS-DA score plot and S-plot reveal altered metabolites following combined therapy with DOX and DZR. The comparative analysis of DD_C and DD_N groups indicates metabolic regulation by DOX + DZR (A), The comparative analysis of DD_C and cancer control groups indicates the metabolic regulation by DOX + DZR in cancerous mice (B), and the comparative analysis of DD_N and normal control groups reveals the unique metabolic effect of DOX and DZR on normal animals.

Fig 8. Cardioprotective effects of DZR on DOX-induced cardiotoxicity involving reprogrammed metabolic pathway.