Induction of caspase‐mediated apoptosis and cell‐cycle G₁ arrest by selenium metabolite methylselenol

Abstract

Previous work based on mono-methyl selenium compounds that are putative precursors of methylselenol has strongly implicated this metabolite in the induction of caspase-mediated apoptosis of human prostate carcinoma and leukemia cells and G1 arrest in human vascular endothelial and cancer epithelial cells. To test the hypothesis that methylselenol itself is responsible for exerting these cellular effects, we examined the apoptotic action on DU145 human prostate cancer cells and the G1 arrest effect on the human umbilical vein endothelial cells (HUVECs) of methylselenol generated with seleno-L-methionine as a substrate for L-methionine-alpha-deamino-gamma-mercaptomethane lyase (EC4.4.1.11, also known as methioninase). Exposure of DU145 cells to methylselenol so generated in the sub-micromolar range led to caspase-mediated cleavage of poly(ADP-ribose) polymerase, nucleosomal DNA fragmentation, and morphologic apoptosis and resulted in a profile of biochemical effects similar to that of methylseleninic acid (MSeA) exposure as exemplified by the inhibition of phosphorylation of protein kinase AKT and extracellularly regulated kinases 1/2. In HUVEC, methylselenol exposure recapitulated the G1 arrest action of MSeA in mitogen-stimulated G1 progression during mid-G1 to late G1. This stage specificity was mimicked by inhibitors of phosphatidylinositol 3-kinase. The results support methylselenol as an active selenium metabolite for inducing caspase-mediated apoptosis and cell-cycle G1 arrest. This cell-free methylselenol-generation system is expected to have significant usefulness for studying the biochemical and molecular targeting mechanisms of this critical metabolite and may constitute the basis of a novel therapeutic approach for cancer, using seleno-L-methionine as a prodrug.

Selenium in cancer prevention: a review of the evidence and mechanism of action

“…2 (adapted from Combs, 2001;Rayman, 2004), from which it can be seen that CH 3 SeH can be formed by the methylation of H 2 Se as part of the Se excretory pathway. There is also some evidence that CH 3 SeH can be formed directly from selenomethionine either by the action of a g-lyase, also known as methioninase (Nakamuro et al 1997;Wang et al 2002;Spallholz et al 2004) or by an a, g-elimination reaction (Okuno et al 2005). Alternatively, it can be formed from a storage form of Se, i.e.…”

Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent

“…Methylselenocysteine (MSC), a stable, water-soluble Se-compound that is quantitatively absorbed when taken orally [18], is then hydrolyzed by a β-lyase to yield methylselenol [2,10,19].…”

The Selenium Metabolite Methylselenol Regulates the Expression of Ligands That Trigger Immune Activation through the Lymphocyte Receptor NKG2D

“…Selenium intervenes with two hallmarks of cancer: apoptosis and angiogenesis. Studies have shown that selenium compounds, most likely CH 3 SeH, can induce caspasemediated apoptosis in cancer cells (37)(38)(39). Angiogenesis is affected by CH 3 SeH precursors because of its inhibition of VEGF from several cancer cell lines (40).…”