Multimodal Mechanism of Antitumoral Ni(II) Thiosemicarbazones: Deep Mechanistic Understanding of ROS Dynamics, Albumin-Mediated Delivery, and DNA Targeting

Cancer accounts for nearly one in four deaths (22.8%) due to noncommunicable diseases globally. The urgency for new effective therapies is worsened by resistance. One strategy is to look for multimodal drugs, which undergo different pathways to achieve selective cytotoxicity. Thiosemicarbazones are known to act as antitumoral compounds through multiple modes of action, and Ni(II) shares some coordination properties with Pt(II) but is also accessible to redox reactions such as superoxide dismutation catalysis. We found that, in a list of four thiosemicarbazone Ni(II) complexes all tested on various cancer cell lines, Ni4 displayed IC50 values down to 5 ± 2 μM and over 8-fold selectivity. We investigated how apoptosis was induced, finding at least two different simultaneous mechanisms both involving the Ni(II) center: first, entrance of the nucleus and coordination of the minor groove of the DNA, modifying its helicity, and second, disruption of the reactive oxygen species (ROS) balance due to the stoichiometric interactions with radical species and catalytic dismutation of hydrogen peroxide, based on the aliphatic N4 substitution that induces a peculiar two-electron exchange reactivity on the Ni(II) center. Even if we found that Ni2 (cytotoxic but nonselective) is as efficient as literature catalase-like mimics (kcat/KM: 10 ± 2 M–1·s–1), Ni4 treatment hits the upregulation of heme oxygenase (HO-1) and mitochondrial superoxide dismutase (SOD-2). Cyclic voltammetry was used to fully characterize both Ni complexes to investigate the mechanisms of the redox processes associated with electron transfer. Clarifying the cytotoxicity mechanisms, we found that the selectivity is related at least to albumin delivery. Albumin, highly concentrated in the mammalian serum, rapidly seizes the compounds and delivers them selectively to the cancer cells. We found that albumin forms a supramolecular complex with the whole coordination compounds, without sequestering the metal ion, and its affinity is highest for Ni4 (Kb: 1.5 ± 0.9 × 106 M–1).