Glutathione-dependent cell cycle G₁ arrest and apoptosis induction in human lung cancer A549 cells caused by methylseleninic acid: comparison with sodium selenite

抄録

The aim of the present study was to clarify the mechanism underlying the inhibition of cell proliferation in human lung cancer A549 cells by selenium (Se) compounds. Methylseleninic acid (CH₃SeO₂H, abbreviated as MSA), a synthetic Se compound, is a direct precursor of active methylselenol (CH₃SeH) and is considered to be one of beneficial agents for cancer prevention and therapy. Sodium selenite (Na₂SeO₃), an inorganic Se form, is utilized in clinical Se supplementation. MSA markedly inhibited the growth of A549 cells at a concentration of 2.5×10^-6 mol/L for 1 day. On Day 1, Na₂SeO₃ also inhibited A549 cell growth at the concentration of 7.5×10^-6 mol/L. These compounds induced cell cycle arrest at the G₁ phase and apoptosis under the inhibitory condition. Reduced glutathione (GSH) is critical to MSA or Na₂SeO₃ metabolism. The depletion of intracellular GSH suppressed Na₂SeO₃-induced G₁ arrest, but promoted Na₂SeO₃-induced apoptosis. Therefore, Na₂SeO₃ appears to have directly induced apoptosis. In contrast, the MSA-induced G₁ arrest was ameliorated by a marked decrease in GSH content. Additionally, the depletion of GSH slightly suppressed MSA-induced apoptosis. The difference in inhibitory effects between MSA and Na₂SeO₃ may be due to this variation in GSH-related metabolism. After exposure of A549 cells to MSA, the GSH content was significantly decreased. These results indicate that because MSA-induced G₁ arrest and apoptosis induction are enhanced by GSH, the maintenance of GSH is essential for the effective anticancer action of MSA in A549 cells.