Se-Methylselenocysteine induces apoptosis through caspase activation in HL-60 cells

Abstract

Apoptosis, a programmed process of cell suicide, has been proposed as the most plausible mechanism for the chemopreventive activities of selenocompounds. In our study, we found that Se-methylselenocysteine (MSC) induced apoptosis through caspase activation in human promyelocytic leukemia (HL-60) cells. Measurements of cytotoxicity, DNA fragmentation and apoptotic morphology revealed that MSC was more efficient at inducing apoptosis than selenite, but was less toxic. Moreover, MSC increased both the apoptotic cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-3 activity, whereas selenite did not. We next examined whether caspases and serine proteases are required for the apoptotic induction by MSC. A general caspase inhibitor, z-VAD-fmk, dramatically decreased cytotoxicity in MSC-treated HL-60 cells and several other apoptotic features, such as, caspase-3 activation, the apoptotic DNA ladder, TUNEL-positive staining and the DNA double-strand break. Interestingly, a general serine protease inhibitor, AAPV-cmk, also effectively inhibited MSC-mediated cytotoxicity and apoptosis. These results demonstrate that MSC is a selenocompound that efficiently induces apoptosis in leukemia cells and that proteolytic machinery, in particular caspase-3, is necessary for MSC-induced apoptosis. On the other hand, selenite-induced cell death could be derived from necrosis rather than apoptosis, since selenite did not significantly induce several apoptotic phenomena, including the activation of caspase-3.

Methylseleninic acid sensitizes prostate cancer cells to TRAIL-mediated apoptosis

“…Recent studies have demonstrated that different selenium-containing compounds activate distinct cell death pathways in cancer cells. MSA-induced nucleosomal DNA fragmentation is accompanied by activation of various caspases, PARP cleavage and mitochondrial release of cytochrome c, whereas apoptotic DNA fragmentation induced by sodium selenite was observed in the absence of detectable caspase activity (Jiang et al, 2001;Kim et al, 2001). Caspases family members are also essential executors of apoptosis induced by Se-(Methyl)selenocysteine (Kim et al, 2001).…”

“…MSA-induced nucleosomal DNA fragmentation is accompanied by activation of various caspases, PARP cleavage and mitochondrial release of cytochrome c, whereas apoptotic DNA fragmentation induced by sodium selenite was observed in the absence of detectable caspase activity (Jiang et al, 2001;Kim et al, 2001). Caspases family members are also essential executors of apoptosis induced by Se-(Methyl)selenocysteine (Kim et al, 2001). In this study, we investigated the mechanism by which MSA augments TRAIL-induced cytotoxicity in prostate cancer cells and demonstrated that MSA modulates expression and activation of proteins involved in cell death signaling through both extrinsic and intrinsic pathways.…”

Bimodal actions of selenium essential for antioxidant and toxic pro-oxidant activities: The selenium paradox (Review)

“…Selenium-induced apoptosis in vascular endothelial cells, leukemia HL-60 cells, prostate DU-145 cancer cells, and murine monocytic RAW264.7 cells activates caspase enzymes (53,(55)(56)(57). DNA fragmentation during the selenium-induced apoptotic process has been reported in various human cancer cell lines including HT29 and SW480 (colonic carcinoma), HepG2 (hepatic carcinoma), A172 and T98G (glioma), and HL-60 (leukemia), as well as the murine monocytic RAW264.7 cell line (57)(58)(59)(60)(61).…”

Irinotecan pharmacokinetic and pharmacogenomic alterations induced by methylselenocysteine in human head and neck xenograft tumors

“…Methylselenocysteine is activated in the liver by h-lyase to its active metabolite methylselenol (24). Methylselenocysteine reportedly induces apoptosis through caspase-3 activation and cleavage of poly(ADPribose) polymerase (25,26), down-regulates inhibitors of apoptosis family proteins, which subsequently enhance apoptosis through Bax cleavage (25), regulates the cell cycle (block cells in S and G 1 phase; refs. 24,27), and reduces DNA synthesis and cell doubling rate (27 -29).…”