Metallomic evaluation of selenium nanoparticles and selenomethionine for the attenuation of cisplatin-induced nephrotoxicity

Abstract

Nephrotoxicity is one of the most limiting side effects in oncologic patients treated with cisplatin and is still clinically unresolved. In this work, chitosan-stabilised selenium nanoparticles (Ch-SeNPs) and selenomethionine (SeMet) have been evaluated as nephroprotectors of cisplatin using renal proximal tubule epithelial cells (RPTEC/TERT1) as a model. Moreover, the antineoplastic efficacy of cisplatin co-administered with these selenocompounds has been tested in cervical cancer cells (HeLa). Cell viability, cell localisation of Ch-SeNPs and changes in the morphology and cell ultrastructure, Pt and Se cellular internalisation and cisplatin binding to DNA, and speciation of Pt and Se in the cytosolic extracts were evaluated by MTT assays, transmission electron microscopy coupled to energy dispersive X-ray spectroscopy (TEM-EDS), inductively coupled plasma mass spectrometry (ICP-MS), and both size exclusion chromatography (SEC) and anion exchange chromatography (AEC) coupled to either ICP-MS or UV-Vis. Differences in the pharmacological activity of the two selenospecies were observed. SeMet exerted a moderate protection on kidney cells while reducing their degree of cisplatin intracellular accumulation and DNA binding in both cell lines, but the antitumour effect of cisplatin was not significantly altered. Conversely, Ch-SeNPs did not impair the Pt-drug uptake or DNA binding in any cell type; and even increased its antitumour effect, which might enable using lower doses of cisplatin without loss of anticancer efficacy, which would result in decreased risk of renotoxicity. Furthermore, cells incubated either with SeMet or SeNPs showed higher levels of selenoproteins, which might enhance cellular defences against the reactive oxygen species (ROS) involved in cisplatin renotoxicity. Hence, both selenocompounds are envisioned as potential coadjuvants to reduce the risk of kidney impairment in future treatments with cisplatin.

Keywords: Chromatography; Cisplatin; Mass spectrometry; Nephroprotection; Selenium nanoparticles; Selenomethionine.