Ni(II) Complexes that Exploit Albumin as Delivery System, Induce DNA Bending, and Disrupt ROS Equilibrium, Unleashing Selective Cytotoxicity Against Lung Carcinoma

Cancer accounts for nearly one in four deaths (22.8%) due to noncommunicable diseases globally. The urgence for new effective therapies is worsened by multi-drug resistance (MDR), which compromises current treatments. One way to face it is looking for multi-modal drugs, which undergo different pathways to achieve selective cytotoxicity. Our complexes consist of thiosemicarbazone ligands arranged around a Ni(II) core: this enables multiple synergistic modes of action, allowing both the metal and ligands to interact with ROS, proteins, and DNA through parallel pathways. We found that, in a list of four complexes, Ni2 and Ni4 displayed a good efficacy in inhibiting cell growth when used on different cancer cell lines, being particularly effective on A549 (lung carcinoma), with up to sixfold selectivity compared to healthy cells. This is probably due to strong interactions with albumin, a major transport protein in mammals enhancing drug delivery to tumors in place of healthy cells. We then looked into the mode of action of Ni2 and Ni4, finding that they both undergo at least two different mechanism simultaneously. Ni2 and Ni4 interact with the minor groove of the DNA both in a cuvette and in the cell nuclei: we compared the circular dichroism spectra of CT-DNA (incubated with Ni2 and Ni4) and DNA extracted from treated A549 cells, finding similar modifications. In addition, Ni2 and Ni4 disrupt the redox balance of cancer cells: they catalyse H2O2 dismutation inducing, and not reducing, oxidative stress. This apparent paradox needed deepening of the RNA expression in treated cells, in the hypothesis of a protein mediated backlash.