Regression Modeling of the Antioxidant-to-Nephroprotective Relation Shows the Pivotal Role of Oxidative Stress in Cisplatin Nephrotoxicity

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.

The Renoprotective Effects of Liraglutide and Alfacalcidol against Cisplatin Induced Nephrotoxicity in Mice

“…Oxidative stress is a pivotal mechanism of CPnephrotoxicity [40]. "Numerous processes and mechanisms lead to CP nephrotoxicity and contribute to its complexity.…”

“…"CP-induced ROS production, which could be a result of neutrophil activation and mitochondrial dysfunction, which can damage cellular macromolecules, including membrane lipids via peroxidation [42]. CP causes oxidative stress by directly damaging mtDNA, which impairs appropriate expression of mitochondrial enzymes forming the respiratory chain, and thus induces oxidative stress" [40]. "The decrease in GSH level and antioxidant enzymes and increase in MDA due to oxidative stress are seen as the main reason for the toxicity caused by CP" [43].…”

Cisplatin for cancer therapy and overcoming chemoresistance

“…The adverse effects of cisplatin treatment include; severe nephrotoxicity [53] that leads to end-stage dialysis, neurotoxicity which arises as ototoxicity [54], vestibulopathy [55] and peripheral neuropathies (that occur less in younger patients) [24]. Cardiovascular co-morbidities arise in cardiomyocytes [56], as hypertension [57], vascular damage [58], and the metabolic syndrome [59].…”

Protective Effect of Natural Antioxidants on Reducing Cisplatin-Induced Nephrotoxicity

“…For over a decade, oxidative stress has been regarded as an important factor that contributes to cisplatin-induced nephrotoxicity [25,26]. Researches showed that cisplatin mainly causes renal damage by inducing oxidative stress in renal tubular and glomerular cells, thereby leading to cell necrosis and apoptosis, vascular dysfunction, and strong immune response [27][28][29][30][31].…”