Antimitogenic and Proapoptotic Activities of Methylseleninic Acid in Vascular Endothelial Cells and Associated Effects on PI3K-AKT, ERK, JNK and p38 MAPK Signaling

ABSTRACT Inhibiting the mitogenic response of vascular endothelial cells may inpart mediate the antiangiogenic and anticancer activity of supranutri-tional selenium supplements. Our previous work had shown that methyl-seleninic acid (MSeA), a precursor of the critical anticancer methylselenolmetabolite pool, was a potent inhibitor of the growth and survival of hu-man umbilical vein endothelial cells (HUVECs). Here we investigated theeffects of MSeA on selected protein kinase signaling transduction path-ways to characterize their role in methylselenium induction of HUVECcell cycle arrest and apoptosis. Exposure of asynchronous HUVECs for30hto3–5 M MSeA led to a profound G 1 arrest, and exposure to higherlevels of MSeA not only led to G 1 arrest but also to DNA fragmentationand caspase-mediated cleavage of poly(ADP-ribose)polymerase, both bio-chemical hallmarks of apoptosis. Immunoblot analyses indicated that G 1 arrest induced by the sublethal doses of MSeA was associated with dose-dependent reductions of the levels of phospho-protein kinase B (alsoknown as AKT or PKB), phospho-extracellular signal regulated kinase(ERK) 1/2, and phospho-Jun NH