Glutathione-Dependent Cell Cycle G(1) Arrest and Apoptosis Induction in Human Lung Cancer A549 Cells Caused by Methylseleninic Acid: Comparison with Sodium Selenite

摘要

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 2.5x10(-6)mol/L for 1 d. On Day 1, Na2SeO3 also inhibited A549 cell growth at the concentration of 7.5x10(-6)mol/L. These compounds induced cell cycle arrest at the G(1) 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 G(1) arrest, but promoted Na2SeO3-induced apoptosis. Therefore, Na2SeO3 appears to have directly induced apoptosis. In contrast, the MSA-induced G(1) 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 G(1) arrest and apoptosis induction are enhanced by GSH, the maintenance of GSH is essential for the effective anticancer action of MSA in A549 cells.