The role of oxidative stress in activity of anticancer thiosemicarbazones

Abstract

Thiosemicarbazones are chelators of transition metals such as iron or copper whose anticancer potency is intensively investigated. Although two compounds from this class have entered clinical trials, their precise mechanism of action is still unknown. Recent studies have suggested the mobilization of the iron ions from a cell, as well as the inhibition of ribonucleotide reductase, and the formation of reactive oxygen species. The complexity and vague nature of this mechanism not only impedes a more rational design of novel compounds, but also the further development of those that are highly active that are already in the preclinical phase. In the current work, a series of highly active thiosemicarbazones was studied for their antiproliferative activity in vitro. Our experiments indicate that these complexes have ionophoric properties and redox activity. They appeared to be very effective generating reactive oxygen species and deregulating the antioxidative potential of a cell. Moreover, the genes that are responsible for antioxidant capacity were considerably deregulated, which led to the induction of apoptosis and cell cycle arrest. On the other hand, good intercalating properties of the studied compounds may explain their ability to cleave DNA strands and to also poison related enzymes through the formation of reactive oxygen species. These findings may help to explain the particularly high selectivity that they have over normal cells, which generally have a stronger redox equilibrium.

Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

“…Another nocodazole may induce mitotic prometaphase arrest by up-regulating the cdc2 levels [ 70 ]. Moreover, prolonged mitotic arrest and cdc2 accumulation have also previously been reported elsewhere [ 71 ]. In addition, both GADD45 and p53 can interact with the p21 CIP/WAF1 protein, which plays a dual role in determining cell fate.…”

High Copper Complex Stability and Slow Reduction Kinetics as Key Parameters for Improved Activity, Paraptosis Induction, and Impact on Drug-Resistant Cells of Anticancer Thiosemicarbazones

“…Significantly, for all of these effects, the interactions with (intracellular) copper pools leading to formation of redox-active copper complexes were suggested to be crucial (16,19,34). Thus, it was proposed that copper complexes induce ROS (superoxide) by redox reaction with intracellular reductants, a mechanism also referred to as "activation by reduction" (11,34,36,44,49). Accordingly, a strong synergism between the metal-free ligand and free copper salts has been repeatedly reported for nanomolar-active TSCs (19,28,49).…”

“…Accordingly, a strong synergism between the metal-free ligand and free copper salts has been repeatedly reported for nanomolar-active TSCs (19,28,49). However, the experiments supporting the ROS model were often performed either with preformed copper(II) complexes (11,34) or by preincubation of the ligands with high levels of extracellular copper (28,36,49). In contrast, in many cases, incubation with the metal-free ligands alone did not induce global ROS detectable for example by the DCF-DA stain (13,28,34).…”

DFT calculations, Hirshfeld surface analysis and docking studies of 3-anisaldehyde thiosemicarbazone

“…4,5 Thiosemicarbazone metal compounds of iron and copper are extensively investigated for their antiproliferative activity. 6,7 Research in the area of treatment of cancer has created a considerable interest among researchers and has rapidly increased in the last few decades. 8,9 The soft donor atoms (N and S) in thiosemicarbazone ligand have the ability to form a chelate compound with suitable metals resulting a potential anticancer drug.…”