Copper(ii) thiosemicarbazone complexes induce marked ROS accumulation and promote nrf2-mediated antioxidant response in highly resistant breast cancer cells

Abstract

A series of water-soluble sodium salts of 3-formyl-4-hydroxybenzenesulfonic acid thiosemicarbazones (or sodium 5-sulfonate-salicylaldehyde thiosemicarbazones) containing different substituents at the terminal nitrogen atom (H, Me, Et, Ph) and their copper(ii) complexes have been prepared and characterised by elemental analysis, spectroscopic techniques (IR, UV-vis, H NMR), ESI mass spectrometry, X-ray crystallography and cyclic voltammetry. The proligands and their copper(ii) complexes exhibit moderate water solubility and good stability in aqueous environment, determined by investigating their proton dissociation and complex formation equilibria. The copper(ii) complexes showed moderate anticancer activity in established human cancer cell lines, while the proligands were devoid of cytotoxicity. The anticancer activity of the copper(ii) complexes correlates with their ability to induce ROS accumulation in cells, consistent with their redox potentials within the biological window, triggering the activation of antioxidation defense mechanisms in response to the ROS insult. These studies pave the way for the investigation of ROS-inducing copper(ii) complexes as prospective antiproliferative agents in cancer chemotherapy.

Induction of cell cycle arrest and apoptosis by copper complex Cu(SBCM)2 towards oestrogen-receptor positive MCF-7 breast cancer cells

“…20 This proposes that the cytotoxicity of Cu(SBCM) 2 could be due to the production of intracellular ROS as copper complex of other variants have found that they induced cell death by induction of high oxidative stress. [21][22][23][24][25] Unexpectedly, based on the DCFH-DA assay results (Fig. 8), Cu(SBCM) 2 did not increase the ROS production in both MCF-7 and MDA-MB-231 cells.…”

Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines

“…In contrast, incubation of cells with 1 and 2 shows a significant (p < 0.0001) increase in the SOD activity. These results indicate that copper complexes can initiate Fenton reactions, intracellularly resulting in ROS accumulation [54,134]. Furthermore, the Cu I ions can react with molecular oxygen and be re-oxidised to Cu II generating reactive superoxide radicals (see Equation 4) and thereby increasing the SOD activity.…”

Palladium(ii) complexes with thiosemicarbazones derived from pyrene as topoisomerase IB inhibitors

“…Furthermore, the coordination of such ligands to palladium could give rise to compounds with a mechanism of action distinct from that of 'cisplatin like' complexes, since thiosemicarbazone derivatives complexes have shown different molecular targets. 5,18,19 In this work, new palladium complexes derived from pyrene thiosemicarbazones were prepared, and designed to have sufficient stability against hydrolysis in solution together with a 'non-cisplatin like' mechanism of action against cancer cells, to overcome the acquired resistance of platinum-based drugs.…”