Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells.

摘要: Interactions between histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), also known as Apo2 ligand, were examined in human leukemia cells (e.g., U937, Jurkat, HL-60). Simultaneous exposure of to 100-ng/ml TRAIL with either 1-mM sodium butyrate or 2- micro M suberoylanilide hydroxamic acid resulted a striking increase leukemic cell mitochondrial damage, caspase activation, apoptosis. Lethal effects significantly diminished U937 ectopically expressing dominant-negative caspase-8, Fas-associated death domain, CrmA (receptor pathway), Bcl-2 Bcl-X(L) (mitochondrial pathway). Analysis events exposed TRAIL/HDAC revealed enhanced Bid activation Bax translocation, loss membrane potential, cytoplasmic release cytochrome c, Smac/DIABLO, factor. No changes observed expression FLICE-like inhibitory protein, receptors, reactive oxygen species generation. inhibitor-induced apoptosis triggered caspase-dependent cleavage p21(WAF1/CIP1); moreover, enforced nuclear localization signal deletant form p21(WAF1/CIP1) lethality. Lastly, p27(KIP1), pRb, X-linked inhibitor apoptosis, displayed extensive proteolysis. These findings indicate that coadministration HDAC synergistically induces myeloid provide further evidence simultaneous the extrinsic intrinsic pathways such leads dramatic injury cascade.