Anticancer activity of diphenyltin(IV) compounds bearing carboxylato N-functionalized 2-quinolones

Abstract

Background: The limited efficacy of conventional metal-based chemotherapeutic drugs is attributed to resistance, high toxicity, and numerous side effects, thus providing a platform for design of new metal-based drugs with enhanced properties. Organotin(IV) compounds have already been recognized as promising agents due to their ability to inhibit tumor growth both in in vitro and in vivo. Following this concept, new diphenyltin(IV) complexes incorporating carboxylato N-functionalized 2-quinolones ligands were assessed on different cancer cell lines. Material and Methods: Evaluation of anticancer activity in vitro of the newly synthesized diphenyltin(IV)complexes bis(3-(4-methyl-2-oxoquinolinyl-1(2H)-l)propanoato)diphenyltin(IV), bis(2-(4-methyl-2-oxoquinolin-1(2H)-yl)ethanoato)diphenyltin(IV), and bis(2-(4-hydroxy-2-oxoquinolin-1(2H)-yl)ethanoato)diphenyltin(IV) (1−3, respectively) as well as ligand precursors (HL1, HL2, and HL3) was determined after 72 h on a panel of cancer cell lines of human and mouse origin (MCF-7, A375, HCT116, 4T1, B16, CT26) using MTT and CV assays. Complex 1 and HCT116 cells were selected for further analysis of the potential mechanism, Flow cytometry for the assessment of cell death, proliferation, caspase activation and production of active oxygen/nitrogen species as well as fluorescent microscopy for detection of nuclei morphology were employed. Results: Obtained results showed a dose-dependent viability decrease in all cell lines exposed to complexes 1−3 with IC50 values in the low micromolar range. Ligand precursors, HL1−HL3 showed no activity up to 200 μM. Complex 1 inhibited cell proliferation and provoked caspase-dependent apoptosis in HCT116 cells. The enhanced presence of autophagosomes determined after the treatment with complex 1 was found to be protective, opposing to apoptosis. The scavenging potential of tested complex 1 on ROS/RNS production can be connected with abolished viability and suppressed proliferation, since HCT116 cells are potent producers of ROS. Conclusions: Taking all together, novel diphenyltin(IV) complexes present promising anticancer agents and should be further tested in vivo.