Intracellular glutathione is a cofactor in methylseleninic acid-induced apoptotic cell death of human hepatoma HEPG(2) cells.
Selenium is a widely studied dietary anticancer agent. Among various selenium compounds, the methylated forms appear to be particularly effective in cancer prevention. Intracellular glutathione (GSH) is known to be involved in the metabolism of many methylated forms of selenium. In this study, we investigated the role of intracellular GSH in methylseleninic acid (MSeA)-induced apoptosis in human hepatoma (HepG(2)) cells. MSeA was shown to deplete intracellular GSH rapidly, preceding the typical apoptotic changes such as DNA fragmentation as measured by the TUNEL assay. When the intracellular GSH concentration was enhanced using N-acetylcysteiene (NAC) (a GSH synthesis precursor) and decreased using buthionine sufoxamine (BSO) (a GSH synthesis inhibitor), NAC markedly augmented MSeA-induced apoptosis, while BSO significantly inhibited MSeA-induced apoptosis. Different from the effect of sodium selenite, there was no measurable superoxide radical level in MSeA-treated cells. These observations suggest that intracellular GSH mainly acts as a cofactor to facilitate MSeA-induced apoptosis, while its antioxidant function becomes largely irrelevant. It is thus postulated that some cancer cells, such as liver cancer cells with higher level of intracellular GSH, would be more susceptible to MSeA cytotoxicity.
Shen
Han-Ming
HM
Department of Community, Occupational, and Family Medicine, National University of Singapore, Republic of Singapore. cofshm@nus.edu.sg
Ding
Wen-Xing
WX
Ong
Choon-Nam
CN
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008113:Liver Neoplasms / Q000473:pathology*; D008163:Luminescent Measurements; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects; D008954:Models, Biological; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D016588:Anticarcinogenic Agents; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C008493:methylselenic acid; D005978:Glutathione