Caspase-inhibited cells induced to die may exhibit the traits of either apoptosis or
necrosis or both, simultaneously. However, mechanisms regulating the commitment to these distinct forms of cell death are barely identified. We found that
staurosporine induced both apoptotic and necrotic traits in U937 cells exposed to the
caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp(OMe)-fluoromethylketone. Morphology and flow cytometry revealed that individual cells exhibited either apoptotic or necrotic traits, but not the mixed phenotype. Inhibition of
cathepsin activity by benzyloxycarbonyl-
Phe-Ala-fluoromethylketone rendered
caspase-compromised cells resistant to
staurosporine-induced apoptosis, but switched the cell death form to
necrosis. Inhibition of
heat shock protein 90 kDa (Hsp90) chaperon activity by
geldanamycin conferred resistance to
necrosis in
caspase-compromised cells but switched the cell death form to apoptosis. Combination of benzyloxycarbonyl-
Phe-Ala-fluoromethylketone and
geldanamycin halted the onset of both forms of cell death by saving mitochondrial trans-membrane potential and preventing acidic volume (lysosomes) loss. These effects of benzyloxycarbonyl-
Phe-Ala-fluoromethylketone and/or
geldanamycin on cell death were restricted to
caspase-inhibited cells exposed to
staurosporine but influenced neither only the
staurosporine-provoked apoptosis nor
hydrogen peroxide (H2O2)-generated
necrosis. Our results demonstrate that the
staurosporine-induced death pathway bifurcates in
caspase-compromised cells and commitment to apoptotic or necrotic phenotypes depends on
cathepsin protease or Hsp90 chaperon activities.