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An Untargeted Metabolomics Approach on Carfilzomib-Induced Nephrotoxicity
Ioanna Barla1, Panagiotis Efentakis2, Sofia Lamprou2
1Laboratory of Analytical Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, 15771 Athens, Greece.
Background:
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.
Methods:
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) (n = 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.
Results:
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.
Conclusions:
Cfz causes metabolite retention in kidney and dysregulates (up and down) several metabolites associated with the occurrence of inflammation and oxidative stress.
Insights
Carfilzomib causes kidney damage by altering metabolites in the kidneys and urine. This study identifies 54 key metabolites linked to inflammation and oxidative stress, clarifying carfilzomib-induced nephrotoxicity mechanisms.
Area of Science:
- Pharmacology
- Toxicology
- Metabolomics
Background:
- Carfilzomib (Cfz) is an anti-cancer drug associated with cardiorenal adverse events.
- Renal complications limit carfilzomib's clinical use, and its nephrotoxicity mechanisms require further clarification.
- Limited metabolomics studies exist on carfilzomib-induced nephrotoxicity.
Purpose of the Study:
- To investigate the metabolomic alterations in mice exposed to carfilzomib.
- To identify potential biomarkers of carfilzomib-induced nephrotoxicity.
- To elucidate the molecular mechanisms underlying carfilzomib nephrotoxicity.
Main Methods:
- UPLC-HRMS-DIA metabolomics applied to plasma, kidney, and urine samples from carfilzomib-treated and control mice.
- Statistical analyses (univariate and multivariate) for biomarker discovery.
- Sub-study to analyze metabolite correlations across bio-samples and explore mechanisms.
Main Results:
- Carfilzomib significantly impacts the kidney and urine metabolome.
- Fifty-four statistically significant metabolites were identified, some linked to renal diseases.
- Metabolome alterations revealed patterns indicative of Cfz toxicity.
Conclusions:
- Carfilzomib induces metabolite retention in the kidney.
- Cfz dysregulates metabolites associated with inflammation and oxidative stress.
- These findings enhance understanding of carfilzomib-induced nephrotoxicity.
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