Discovery of Potential Biomarkers with Dose- and Time-Dependence in Cisplatin-Induced Nephrotoxicity Using Metabolomics Integrated with a Principal Component-Based Area Calculation Strategy

Cisplatin is a potent chemotherapeutic agent. However, its clinical usage is restricted by serious adverse effects, especially nephrotoxicity. For revealing the dose- and time-dependence of cisplatin-induced nephrotoxicity, mass spectrometry based metabolomics integrated with a principal component-based area calculation (PCAC) strategy was proposed in the present study. Area plots based on the first two principal components of the principal component analysis model were constructed first. Then, the sums of cumulative areas under PC-T curves (AUC(PC-T)) were calculated. Finally, the fold change of AUC(PC-T) between experimental and control groups at different time points was calculated and used as an indicative parameter. With the PCAC approach, dose- and time-dependence of cisplatin-induced metabolic change was quantitatively confirmed for the first time. Furthermore, 27 potential biomarkers with dose- and time-dependence related to nephrotoxicity induced by cisplatin were screened out and tentatively identified. Metabolic pathways interrupted by cisplatin mainly included energy, amino acid, and lipid metabolism.