ABSTRACT
Nephrotoxicity is a major complication of cisplatin-based chemotherapy, leading to acute kidney injury in ca. 30% of patients, with no preventive intervention or treatment available for clinical use. Cilastatin has proved to exert a nephroprotective effect for cisplatin therapies in in vitro and in vivo models, having recently entered clinical trials. A deeper understanding at the molecular level of cisplatin-induced renal damage and the effect of potential protective agents could be key to develop successful nephroprotective therapies and to establish new biomarkers of renal damage and nephroprotection. A targeted lipidomics approach, using LC-MS/MS, was employed for the quantification of 108 lipid species (comprising phospholipids, sphingolipids, and free and esterified cholesterol) in kidney cortex and medulla extracts from rats treated with cisplatin and/or cilastatin. Up to 56 and 63 lipid species were found to be altered in the cortex and medulla, respectively, after cisplatin treatment. Co-treatment with cilastatin attenuated many of these lipid changes, either totally or partially with respect to control levels. Multivariate analysis revealed that lipid species can be used to discriminate renal damage and nephroprotection, with cholesterol esters being the most discriminating species, along with sulfatides and phospholipids. Potential diagnostic biomarkers of cisplatin-induced renal damage and cilastatin nephroprotection were also found.
Subject(s)
Acute Kidney Injury/drug therapy , Cilastatin/pharmacology , Kidney/drug effects , Lipids/genetics , Acute Kidney Injury/genetics , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Animals , Apoptosis/drug effects , Chromatography, Liquid , Cisplatin/adverse effects , Glomerular Filtration Rate/drug effects , Humans , Kidney/pathology , Lipid Metabolism/genetics , Lipidomics , Rats , Tandem Mass SpectrometryABSTRACT
Pt-containing drugs are nowadays essential components in cancer chemotherapy. However, drug resistance and side effects limit the efficiency of the treatments. In order to improve the response to Pt-based drugs, different administration strategies or new Pt-compounds have been developed with little success. The reason for this failure could be that the mechanism of action of these drugs is not completely understood. In this way, metallomics studies may contribute to clarify the interactions of Pt-containing drugs within the organism. This review is mainly focused on the role of Analytical Chemistry on the study of the interactions between Pt-based drugs and biomolecules. A summary of the analytical techniques and the most common sample treatment procedures currently used in metallomics studies of these drugs is presented. Both are of paramount importance to study these complex samples preserving the drug-biomolecule interaction. Separation and detection techniques must be carefully selected in order to achieve the intended goals. The use of multidimensional hyphenated techniques is usually necessary for a better understanding of the Pt-based drugs interactions in the organism. An overview of Pt-drugs biological interactions is presented, considering the different sample matrices and the drugs course through the organism. Samples analysed in the included studies are blood, urine, cell cytosol, DNA as well as the drugs themselves and their derivatives. However, most of these works are based on in vitro experiments or incubations of standards, leading in some cases to contradictory results depending on the experimental conditions used. Though in vivo experiments represent a great challenge due to the high complexity and the low concentrations of the Pt-adducts in real samples, these studies must be undertaken to get a deeper understanding of the real interactions concerning Pt-containing drugs.
