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Rosato, R.R., Almenara, J.A., Dai, Y. & Grant, S. 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. Mol. Cancer Ther. 2, 1273-1284

Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
Molecular Cancer Therapeutics (Impact Factor: 6.11). 01/2004; 2(12):1273-84.
Source: PubMed

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

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    • "It has been reported that inhibition of histone deacetylases (HDACs) that reverses aberrant epigenetic changes have emerged as a potential strategy to sensitize cancer cells for TRAIL-induced apoptosis [18]. HDAC inhibitors have been shown to synergize with TRAIL in a variety of human cancers by inducing DR4 and DR5 through NF-kB activation and some of the proapoptotic members of the Bcl-2 family, and engaging the mitochondrial pathway such as enhanced BID activation and Bax translocation, loss of mitochondrial membrane potential, and cytoplasmic release of cytochrome c, Smac/DIABLO, and apoptosis-inducing factor [19] [20] [21], although the different synergy mechanisms may be dependent on the cell type or the particular HDACI used [22]. However, inhibitor of class III HDAC such as SIRT1 inhibitor has not been reported to augment TRAILinduced apoptosis and its mechanism. "
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    • "Notably, early results of trials combining HDAC with proteasome inhibitors have shown promise in patients with refractory multiple myeloma (Badros et al 2009), and such efforts are being expanded in other malignancies. In preclinical studies, synergistic interactions between HDACis and TRAIL have been attributed to up-regulation of death receptors (Insinga et al 2005) and/or to simultaneous interruption of the intrinsic and extrinsic apoptotic pathways (Rosato et al 2003a). In addition, pan-HDACis that prevent tubulin and Hsp90 deacetylation have been shown to interact synergistically with tyrosine kinase inhibitors targeting oncogenic proteins requiring chaperone function for their survival e.g., Bcr/Abl (Bali et al 2005, Yu et al 2003). "
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    • "Accumulation of ROS occurs in transformed cells cultured with HDACis, such as Vorinostat, TSA, butyrate, or MS- 275 (Rosato et al. 2003; Ruefli et al. 2001; Ungerstedt et al. 2005; Xu et al. 2006). Accumulation of ROS might play an important role in HDACi-induced cell death. "
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