Thiosemicarbazone-metal complexes exhibiting cytotoxicity in colon cancer cell lines through oxidative stress

Colorectal cancer is the third most common type of cancer and has a high incidence in developed countries. At present, specific treatments are being required to allow individualized therapy depending on the molecular alteration on which the drug may act. The aim of this project is to evaluate whether HPTSC and HPTSC* thiosemicarbazones (HPTSC = pyridine-2-carbaldehyde thiosemicarbazone and HPTSC* = pyridine-2-carbaldehyde 4N-methylthiosemicarbazone), and their complexes with different transition metal ions as Cu(II), Fe(III) and Co(III), have antitumor activity in colon cancer cells (HT-29 and SW-480), that have different oncogenic characteristics. Cytotoxicity was evaluated and the involvement of oxidative stress in its mechanism of action was analyzed by quantifying the superoxide dismutase activity, redox state by quantification of the thioredoxin levels and reduced/oxidized glutathione rate and biomolecules damage. The apoptotic effect was evaluated by measurements of the levels of caspase 9 and 3 and the index of histones. All the metal-thiosemicarbazones have antitumor activity mediated by oxidative stress. The HPTSC*-Cu was the compound that showed the best antitumor and apoptotic characteristics for the cell line SW480, that is KRAS gene mutated. Cytotoxicity ranking on colon cancer cell lines (HT-29 and SW480) with free and metal coordinated thiosemicarbazones. These compounds cause changes in oxidative stress levels in several metabolic points leading to cell death. [Display omitted] •Cytotoxicity increases significantly when thiosemicarbazone ligands link metal ions.•Complexes formed by thiosemicarbazones and Cu(II) have the most proapoptotic activity.•The methylated Cu(II)-derivative acts in DNA in a prooxidant way and induces apoptosis.