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: 5.68). 01/2004; 2(12):1273-84.
Source: PubMed


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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Available from: Yun Dai, Oct 08, 2014
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    • "Histone deacetylase inhibitors (HDACi) act through their modulation of the epigenetic silencing [23], and recent reports have shown that HDACis co-operate with other therapies, including TRAIL, leading to the activation of cell death pathways in various cancer models [23]–[27]. HDACis’ co-operation with TRAIL has been shown to occur mainly through increased expression of death receptors, particularly DR5 [7], [24] and in some cases by increased expression of DR4 [10], [28]. In addition to its cooperation with TRAIL, its reported brain access [29] makes it a potential candidate for MB therapies, however characterization of its efficacy in MB mouse models still remains to be explored. "
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    • "HDAC inhibitors are able to activate apoptosis, either via the extrinsic (death receptor) pathway or intrinsic (mitochondrial) pathway or both in many cancer types and models (Rosato et al., 2003). The extrinsic pathway is activated through ligands, such as TRAIL or FASL, binding to their death receptors. "
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    • "HDACIs act mainly via the death receptor pathway (extrinsic) or mitochondrial pathway (intrinsic) to activate caspase and induce tumor cell apoptosis [12]. The increasing levels of the death receptor ligands FasL and TRAIL caused by HDACIs are not observed in normal cells, suggesting the selectivity of HDACIs. "
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