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

Apoptosis, a programmed process of cell suicide, has been proposed as the m ost plausible mechanism for the chemopreventive activities of selenocompoun ds, In our study, we found that Se-methylselenocysteine (MSG) induced apopt osis through caspase activation in human promyelocytic leukemia (HL-60) cel ls. Measurements of cytotoxicity, DNA fragmentation and apoptotic morpholog y revealed that MSC was more efficient at inducing apoptosis than selenite, but was less toxic. Moreover, MSG increased both the apoptotic cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-3 activity, whereas selenit e did not. We next examined whether caspases and serine proteases are requi red for the apoptotic induction by MSG. A general caspase inhibitor, z-VAD- fmk, dramatically decreased cytotoxicity in MSG-treated HL-60 cells and sev eral other apoptotic features, such as, caspase-3 activation, the apoptotic DNA ladder, TUNEL-positive staining and the DNA double-strand break. Inter estingly, a general serine protease inhibitor, AAPV-cmk, also effectively i nhibited MSG-mediated cytotoxicity and apoptosis, These results demonstrate that MSC is a selenocompound that efficiently induces apoptosis in leukemi a cells and that proteolytic machinery, in particular caspase-3, is necessa ry for MSC-induced apoptosis, On the other hand, selenite-induced cell deat h could be derived from necrosis rather than apoptosis, since selenite did not significantly induce several apoptotic phenomena, including the activat ion of caspase-3.