Oxidative imbalance linked to impaired mitochondrial bioenergetics mediates the toxicity of mesoionic compounds MI-D and MI-J in hepatocarcinoma cells (HepG2)

Hepatocellular carcinoma (HCC) is a common and deadly form of liver cancer with limited treatment options for advanced stages. Mesoionic compounds MI-D and MI-J have shown potential for treating HCC due to their significant toxicity to these cells. This study investigated whether this toxicity is linked to their effects on oxidative balance in HepG2 cells cultured in high glucose (HG-glycolysis-dependent) and galactose plus glutamine supplemented (GAL-oxidative phosphorylation-dependent) DMEM medium. ROS levels were increased in cells cultured in both media when exposed to MI-D and MI-J (50 μM). However, MI-D at an intermediate concentration (25 μM) decreased ROS levels in the GAL medium. Superoxide dismutase (SOD) activity increased under all tested conditions by compounds (25 μM). Conversely, MI-D and MI-J decreased total peroxidase activity in both media at 25 and 50 μM, respectively. MI-D in the HG medium decreased glutathione peroxidase (GPX) activity, whereas MI-J reduced the enzyme activity at a concentration of 25 μM and increased it at 50 μM. In the GAL medium, MI-J (50 μM) increased GPx activity, while glutathione reductase (GR) activity was decreased by the compounds (50 μM) in both media. Furthermore, the P-AMPK/tAMPk ratio was increased by MI-J at 25 μM in the GAL medium. Our results show that MI-D and MI-J caused oxidative imbalance, particularly affecting cells cultured in the GAL medium. The data also support that the mesoionic effects depended on their concentration and substituent in the mesoionic ring.