An Untargeted Metabolomics Approach on Carfilzomib-Induced Nephrotoxicity

• Published in: Molecules (Basel, Switzerland) Vol. 27; no. 22; p. 7929
• Main Authors: Barla, Ioanna, Efentakis, Panagiotis, Lamprou, Sofia, Gavriatopoulou, Maria, Dimopoulos, Meletios-Athanasios, Terpos, Evangelos, Andreadou, Ioanna, Thomaidis, Nikolaos, Gikas, Evangelos
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.11.2022; MDPI
• Subjects: Analysis; Animals; Biomarkers; Cardiotoxicity; Carfilzomib; Clinical medicine; Complications; Complications and side effects; Datasets; HRMS; Kidney; Kidney diseases; Kidneys; Laboratory animals; Metabolism; Metabolites; Metabolome; Metabolomics; Mice; Multivariate analysis; nephrotoxicity; Oligopeptides; Oxidative stress; Plasma; Samples; Sodium chloride; Statistical analysis; Targeted cancer therapy; Tocopherols; Urine; Germany; HRMS; nephrotoxicity; metabolomics; carfilzomib
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27227929

Carfilzomib (Cfz) is an anti-cancer drug related to cardiorenal adverse events, with cardiovascular and renal complications limiting its clinical use. Despite the important progress concerning the discovery of the underlying causes of Cfz-induced nephrotoxicity, the molecular/biochemical background is still not well clarified. Furthermore, the number of metabolomics-based studies concerning Cfz-induced nephrotoxicity is limited. A metabolomics UPLC-HRMS-DIA methodology was applied to three bio-sample types i.e., plasma, kidney, and urine, obtained from two groups of mice, namely (i) Cfz (8 mg Cfz/ kg) and (ii) Control (0.9% NaCl) ( = 6 per group). Statistical analysis, involving univariate and multivariate tools, was applied for biomarker detection. Furthermore, a sub-study was developed, aiming to estimate metabolites' correlation among bio-samples, and to enlighten potential mechanisms. Cfz mostly affects the kidneys and urine metabolome. Fifty-four statistically important metabolites were discovered, and some of them have already been related to renal diseases. Furthermore, the correlations between bio-samples revealed patterns of metabolome alterations due to Cfz. Cfz causes metabolite retention in kidney and dysregulates (up and down) several metabolites associated with the occurrence of inflammation and oxidative stress.