Abstract
The clinical utility of the chemotherapeutic drug cisplatin is significantly limited by its nephrotoxicity, which is characterized by electrolytic disorders, glomerular filtration rate decline, and azotemia. These alterations are consequences of a primary tubulopathy causing injury to proximal and distal epithelial cells, and thus tubular dysfunction. Oxidative stress plays a role in cisplatin nephrotoxicity and cytotoxicity, but its relative contribution to overall toxicity remains unknown. We studied the relation between the degree of oxidative reduction (provided by antioxidant treatment) and the extent of nephrotoxicity amelioration (i.e., nephroprotection) by means of a regression analysis of studies in animal models. Our results indicate that a linear relation exists between these two parameters, and that this relation very nearly crosses the value of maximal nephroprotection at maximal antioxidant effect, suggesting that oxidative stress seems to be a pivotal and mandatory mechanism of cisplatin nephrotoxicity, and, hence, an interesting, rationale-based target for clinical use. Our model also serves to identify antioxidants with enhanced effectiveness by comparing their actual nephroprotective power with that predicted by their antioxidant effect. Among those, this study identified nanoceria, erythropoietin, and maltol as highly effective candidates affording more nephroprotection than expected from their antioxidant effect for prospective clinical development.
Highlights
Cisplatin is one of the most potent and widely used chemotherapeutic drugs for the treatment of a variety of solid cancers [1], but its dosage and clinical utility are limited by nephrotoxicity [2]
We studied and modeled the relation between the degree of reduction in oxidative stress and the degree of protection of cisplatin nephrotoxicity bestowed by exogenous antioxidants in a number of studies with animal models
The data used for this study were obtained from the literature search carried out in our previous meta-analysis [41], in which preclinical studies reporting molecules or products preventing cisplatin nephrotoxicity were identified
Summary
Cisplatin is one of the most potent and widely used chemotherapeutic drugs for the treatment of a variety of solid cancers [1], but its dosage and clinical utility are limited by nephrotoxicity [2]. Tubular damage causes a reduction in glomerular filtration rate (GFR) by a number of mechanisms, including activation of the tubuloglomerular feedback (TGF) mechanism and renal vasoconstriction induced by inflammation and factors released by activated renal cells [2,10]. This pathophysiological pattern results from cisplatin accumulation in proximal (mainly the S3 segment) [11,12] and distal tubule cells [2,13], which causes diverse cellular alterations, including inhibition of membrane transporters [2,14], interference with metabolic pathways [15], and cell death [16,17]. Cisplatin becomes aquated and turns into a potent nucleophilic that binds to numerous targets, most prominently nucleic acids and many proteins [18,20]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
