Overexpression of Bcl-X(L) inhibits Ara-C-induced mitochondrial loss of cytochrome c and other perturbations that activate the molecular cascade of apoptosis.

摘要: High-dose Ara-C (HIDAC) induces the cleavage and activity of caspase-3 (CPP32β/Yama/apopain), resulting in morphological biochemical features apoptosis. High levels antiapoptotic Bcl-xL or Bcl-2, relative to proapoptotic Bax, have been shown inhibit HIDAC-induced apoptosis human acute myeloid leukemia HL-60 cells. In a previous report, we demonstrated this inhibition, using control (HL-60/neo) cells their counterparts, HL-60/Bcl-xL, which enforced overexpression significantly lower ratio free bound Bax. Results present studies demonstrate that, initiation phase HL-60/neo due HIDAC (10 100 µm for 4 h), cytochrome c is released from mitochondria cytosol, followed by loss mitochondrial membrane potential (ΔΨm) an increase reactive oxygen species; these events precede trigger caspase-3. These early cytosolic perturbations, represent apoptosis, were inhibited HL-60/Bcl-xL treatment h also modestly increased intracellular Bax Bcl-2 but not cells, progressive accumulation decrease ΔΨm, species coculture with tetrapeptide inhibitors caspases that previously Ara-C-induced findings indicate inhibits preapoptotic prevent thereby preserving inactive zymogen state checking molecular cascade