A meta-analysis of preclinical studies using antioxidants for the prevention of cisplatin nephrotoxicity: implications for clinical application

Abstract

Cisplatin is an effective chemotherapeutic drug whose clinical use and efficacy are limited by its nephrotoxicity, which affects mainly the renal tubules and vasculature. It accumulates in proximal and distal epithelial tubule cells and causes oxidative stress-mediated cell death and malfunction. Consequently, many antioxidants have been tested for their capacity to prevent cisplatin nephrotoxicity. In this study, we made a systematic review of the literature and meta-analyzed 152 articles, which tested the nephroprotective effect of isolated compounds or mixtures of natural origin on cisplatin nephrotoxicity in preclinical models. This meta-analysis identified the most effective candidates and examined the efficacy obtained by antioxidants administered by the oral and intraperitoneal routes. By comparing with a recent, similar meta-analysis performed on clinical studies, this article identifies a disconnection between preclinical and clinical research, and contextualizes, discusses, and integrates the existing preclinical information toward the optimized selection of candidates to be further explored (clinical level). Despite proved efficacy, this article discusses the barriers limiting the clinical development of natural mixtures, such as those in extracts from Calendula officinalis flowers and Heliotropium eichwaldii roots. On the contrary, isolated compounds are more straightforward candidates, among which arjunolic acid and quercetin stand out in this meta-analysis.

Keywords:

• Cisplatin
• nephrotoxicity
• prevention
• antioxidants
• preclinical
• meta-analysis

Acknowledgements

The authors acknowledge the anonymous reviewers for their constructive comments and suggestions that have helped to improve the final version of the manuscript.

Declaration of interest

This article was funded by grants from Instituto de Salud Carlos III [PI17/01979, PI18/00996], and the Kidney Research Network REDINREN [RD016/0009/0025], and FEDER funds. The authors report no conflict of interests. The author’s affiliation is as shown on the cover page. The authors have sole responsibility for the writing and content of the paper. None of the authors have in the last 10 years appeared in any legal proceedings related to the contents of this paper.