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

• Published in: Carcinogenesis (New York) Vol. 22; no. 4; pp. 559 - 565
• Main Authors: Kim, Taeho, Jung, Uhee, Cho, Dae-Yeon, Chung, An-Sik
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-04-2001; Oxford Publishing Limited (England)
• Subjects: AAPV-cmk; Ala-Ala-Pro-Val-chloromethylketone; Amino Acid Chloromethyl Ketones - metabolism; Anticarcinogenic Agents - pharmacology; Antineoplastic agents; Apoptosis; Asp-Glu-Val-Asp-p-nitroanilide; Biological and medical sciences; Caspase 3; Caspases - metabolism; Chemotherapy; Cysteine - analogs & derivatives; Cysteine - pharmacology; DEVD-pNA; DNA Damage; DNA Fragmentation; Dose-Response Relationship, Drug; Enzyme Activation; HL-60 Cells; Humans; Immunoblotting; In Situ Nick-End Labeling; lactate dehydrogenase; LDH; Medical sciences; MSC; N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone; Organoselenium Compounds - pharmacology; PARP; Pharmacology. Drug treatments; poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - metabolism; Se-methylselenocysteine; Selenocysteine - analogs & derivatives; Sodium Selenite - pharmacology; terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; Time Factors; TUNEL; z-VAD-fmk; Antineoplastic agent; Cysteine endopeptidases; Glycosyltransferases; Fragmentation; Double strand break; Signal transduction; Established cell line; ADP-ribosyltransferase; Tumor cell; Human; Promyelocytic leukemia; Enzyme; Transferases; Acute; Malignant hemopathy; In vitro; Biological activity; NAD; Peptidases; Chromosome break; Single strand break; Cell death; DNA; Selenium compound; Hydrolases; Pentosyltransferases; Apoptosis
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/22.4.559

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.