Biol. Pharm. Bull. 28(4) 757—759 (2005)

has been studied in in vitro and in vivo experimental models. Zn has both pro-apoptotic effects and anti-apoptotic effects. While Zn attenuated the induction of apoptosis by glucocorticoid at 0.5—5.0 mM, Zn induced apoptosis at 80—200 mM in mouse thymocytes. On the contrary, Zn at concentrations of 10 to 50 mM attenuated manganese-induced apoptosis, but higher concentrations of Zn (50—100 mM) increased cell death in human Burkitt lymphoma B cells. Zn had no effect on interleukin-3-mediated apoptosis in murine B lymphoid cells but enhanced CD95-mediated apoptosis in human T lymphoid cells. Thus, Zn has opposite effects on the induction of apoptosis, but the mechanism by which Zn affects apoptosis remains unclear. Caspases are a conserved family of cysteine proteases that play pivotal roles in apoptosis. Caspases are present as proenzymes that are readily cleaved and activated during apoptosis, providing the cell with a means to rapidly amplify its apoptotic response. Three fundamental caspase-activating pathways in mammalian cell apoptosis have been identified: (1) a pathway in which mitochondrial functional integrity is altered, (2) a pathway in which extracellular death receptors are coupled to cytoplasmic death domains, and (3) a pathway in which caspase is activated in the endoplasmic reticulum. Regardless of the apoptotic-activating pathway, caspase-3 appears to be the point of intersection for caspase-mediated cell death leading to the conserved apoptotic morphology. As a primary executor caspase, caspase-3 is responsible for many of the death foci related to apoptosis, including the induction of DNA damage and poly (ADP-ribose) polymerase (PARP) cleavage. The effect of Zn on apoptosis induction has been mainly investigated in cells treated with apoptotic stimuli, including some antitumor agents and geranylgeraniol. Inhibitory effects of Zn on the induction of apoptosis were observed with inhibition of apoptotic stimuli-mediated activation of caspase-3. Previously, we found that an influx of Zn into the cell, which was mediated by a Zn ionophore (Py, pyrithione) and Zn, induced apoptosis via activation of caspases in human leukemia HL-60 cells. Although a broad-spectrum inhibitor of caspases attenuated Py/Zn-induced apoptosis, the involvement of caspase-3 in Py/Zn-induced apoptosis is obscure. In the present study, we investigated the activation of caspase-3 in Py/Zn-treated cells and estimated the involvement of caspase-3 in Py/Zn-induced apoptosis.