A type of cystein proteases, called caspases are the main regulators of apoptosis. However, more and more data support the idea that the inhibition of caspase activity is not by all means sufficient to inhibit cell death. These caspase activity-independent cell death forms may be diverse according to morphological and even biochemical studies. Increasing amount of evidence suggests that the alternative forms of cell death are actively regulated by cells and in some cases their role in physiological and developmental situations has also been demonstrated. However, the regulator components and mechanisms of caspase-compromised cell death are less understood. Knowledge of these alternative cell death pathways may help us to overcome chemotherapy resistance of tumors or to decrease the intensity of necrosis resulting in secondary tissue damage.;By examining alternative cell death pathways we found that staurosporine (STS), a model compound of apoptotic death, resulted in both apoptotic and necrotic cell death even in the presence of z-VAD.fmk, a caspase inhibitor. Light microscopic and flow cytometry analysis confirmed that the two distinct forms of cell death occurred in parallel in separate cells. Inhibition of cystein cathepsins by z-FA.fmk prevented STS induced apoptosis in caspase-inhibited cells, however, cells did not survive but died with necrosis. Inhibition of Hsp90 chaperon activity with geldanamycin (GA) blocked necrotic cell death in caspase compromised cells. In this case cells died with apoptosis. Cotreatment with z-FA.fmk and GA inhibited both forms of caspase compromised cell death by preserving mitochondrial membrane potential and lysosomes. Cotreatment with these two inhibitors was not effective in the inhibition of STS only induced (caspase dependent) apoptosis and H2O2 stimulated necrosis, indicating the specificity of inhibitors.;In conclusion, STS induced cell death diverges in STS treated, caspase-inhibited U937 cells. Decision between the two types of death might depend on the activity of cystein cathepsins and the Hsp90 chaperon protein.
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