Biological evaluation of chlorogold complexes as potential anti-tumoural compounds: unraveling mechanisms of action

Abstract

Cytotoxic chemotherapyat the present state is set asthe traditional hallmark of oncological treatment;however host toxicity and drug resistance acquisition remainas main challengesto overcome.Over the past few years there has been a great effort towards findingnew chemotherapeutic compounds with improvedpharmacodynamic and pharmacokinetic properties in order to achieve higher cancer specificityandreducedundesirable side effects. The present work intendedtocharacterize andelucidate the anti-tumouraleffect of chlorogold complexes bearing phosphineor N,O-donor ligands, and explorethe mechanisms by which they exert their antiproliferative propertiesas a part of this effort.Chloro(trimethylphosphine)gold(I)and Chloro(triphenylphosphine)gold(I)in vitrocell viability assays in A549 tumour cell line exhibited IC50valuesof 44.4 and 30.0μMrespectively, plus3.3 and, 5.4 μMin H1975 respectively.Predisposition of the chlorogold complexesto targetnon-tumoural cells,evaluated in fibroblastsnormal cell line,revealed an IC50value of 7.7 and 19.1μMrespectively.Apoptosismorphological featureswerealso confirmed. A549 and H1975 cell line exposure to both chlorogold complexes at their respective IC50values, revealed nuclear fragmentation and chromatin condensation, observed by Hoechst 33258 staining. These results were furtherprovenforby flow cytometry analysis. Double staining with Annexin V-FITC and PropidiumIodide in A549after compound exposurerevealed the ability to induce mechanisms of cell death by apoptosis in a dose-dependent fashion. Chloro(triphenylphosphine)gold(I) was further proven to be able to induce cell cycle delay, this effect being especially evident for S-phase. Moreovercompound interaction with the DNA molecule was proven to be either weak or inexistent through electrophoretic mobility assayrevealedbythe compounds’ inability to compromise plasmidDNA conformation. Proteomic studieseven though not conclusive regarding chlorogold compounds’ mechanism of action,allowed the identification of new potential biomarkers for prediction of prognosisin non-small-cell lung carcinoma.