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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    • "In the death receptor mediated apoptosis, FADD-caspase-8 pathway, caspase-8 activation would either activate caspase-3/7 directly or through caspase-9 or simultaneously[37]. The exact mechanism of simultaneous activation of both pathways has yet to be elucidated but is reported frequently in cancer drug discovery research[35,38,39]. In this study in particular, caspase-8 was activated immediately after the treatment and followed by caspase-3/7 activation. "
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    • "In addition, the expression of pro-and anti-apoptotic proteins that regulate the TRAIL-induced death pathway is modulated after HDACi treatment. Increased expression/activation of caspase-8, Bid and Bax has been reported after HDACi treatment (Rosato et al., 2003; Inoue et al., 2004; Hacker et al., 2009; Fulda, 2012; Riley et al., 2013), as well as downregulation of cFLIP and anti-apoptotic Bcl-2 family proteins (Zhang et al., 2003; Watanabe et al., 2005; Gillespie et al., 2006). Besides proteasome inhibitors and HDACi, numerous studies have demonstrated the ability of standard chemotherapeutic drugs to increase tumor cell sensitivity to TRAIL receptor agonists (Mom et al., 2009; Newsom-Davis et al., 2009; Rajeshkumar et al., 2010; Cohn et al., 2013). "
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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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