Novel Organic Selenium Compounds With Antioxidant Activities Reverse Cisplatin-induced Nephrotoxicity And The Underlying Mechanisms

Cisplatin is one of the most widely used and most potent chemotherapy drugs.However, side effects in normal tissues and organs, notably nephrotoxicity in thekidneys, limit the use of cisplatin and related platinum-based therapeutics. Oxidativestress injury is actively involved in the pathogenesis of cisplatin-induced kidney injury.The strong antioxidant activity of organic selenocomponds has been supported by manyresearches.The aim of this study is to search for organic selenocomponds withantioxidant activities to reverse nephrotoxicity induced by cisplatin and to elucidate themolecular mechanisms. In this study the red blood cells were treated with AAPH asoxidation model. The antioxidant activity of the selenium-contained allophycocyanin(Se-APC), and its protective efferts on the red blood cells and the underlyingmechanisms were studied. The protect effects of organic selenocomponds with strongantioxidant activity such as DsePA, against cisplatin induced nephrotoxicity was alsostudied, and the underlying molecular mechanisms were also elucidated in this study.The findings of this study were summarized following:1. The result of ABTS+free radical scavenging assay showed that Se-APC had strongfree radical scavenging capacity. The oxidative hemolysis and morphologicalchanges induced by AAPH in human erythrocytes were efectively reversed bypre-incubation with Se-APC. Lipid oxidation induced by the prooxidant agent cupricchloride in human plasma was also blocked by Se-APC, which was comfirmed byevaluating the formation of conjugated diene. The accumulation of malondialdehyde,loss of reduced glutathione, and increase in enzyme activities of glutathioneperoxidase and reductase induced by AAPH in human erythrocytes were effectivelysuppressed by Se-APC. Furthermore, Se-APC significantly preventedAAPH-induced intracellular reactive oxygen species (ROS) generation. Our resultssuggest that Se-APC demonstrates application potential in treatment of diseases inwhich excess production of ROS, Se-APC could acts as a casual or contributoryfactor. Taken together, this study set up a convenient and effective method to evaluate the antioxidant activities of tested compounds.2.3,3′-diselenodipropionic acid (DSePA) is a selenocysteine derivative exihibitingstrong antioxidant activity. In this experment we found that DSePA can protectHK-2cells from cisplatin-induced nephrotoxicity by inhibiting intracellular ROSgeneration and activating of Akt pathway. The effect of reducing agent GSH wasdemonstrated similar effect to that of DSePA. The result of flow cytometric analysisrevealed that DSePA could reduce the percentage of apoptotic cells induced bycisplatin. DSePA also suppressed the activation of Caspase-3and cleavage of PARPwas determined by Western blotting. In addition, DSePA blocked thecisplatin-induced mitochondrial dysfuaction and activation of death receptor-mediated apoptotic pathway. The results of Western blot analysis and thefluorescence staining assay showed that DSePA prevented cisplatin-inducedreduction of mitochondrial membrane potential and mitochondrial mass. DSePAalso reversed the changes on the expressing levels of Bcl-2family proteins that werechanged by cisplatin. Moreover, cisplatin-induced activation of Caspase-8/10wasblocked by DSePA. Interestingly, DSePA didn’t affect the effect of cisplatin oncancer cells, suggesting its future application potential in medicine.