Histone deacetylase inhibitors as anti-neoplastic agents

Batty, Nicolas; Malouf, Gabriel G.; Issa, Jean–Pierre J.

doi:10.1016/j.canlet.2009.03.013

Cited by 135 publications

(107 citation statements)

References 75 publications

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“…HDACIs, which are promising, tumor-killing anti-cancer agents with low toxicity against normal cells, can also potentiate TRAIL-induced apoptosis in leukemia cells through multiple cellular mechanisms that affect both the extrinsic and intrinsic apoptotic pathways in various tumor types [3,16]. SAHA has been approved by the U.S. Food and Drug Administration for the treatment of cutaneous T cell lymphoma and other various HDACIs are now under Phase I/II clinical trials as a single agent or in combination with other agents [16,38].…”

Section: Discussionmentioning

confidence: 99%

“…SAHA has been approved by the U.S. Food and Drug Administration for the treatment of cutaneous T cell lymphoma and other various HDACIs are now under Phase I/II clinical trials as a single agent or in combination with other agents [16,38]. Our study demonstrated that the HDACIs, SAHA and VPA, significantly enhance both AY4-and TRAIL-induced caspase-dependent apoptotic cell death in CEM-CM3 and CCRF-CEM cells, mainly through downregulation of anti-apoptotic proteins (c-FLIP, Bcl-2, Bcl-X L , XIAP, and survivin) without significantly changing expression levels of the pro-apoptotic proteins Bax and Bak or the death receptors DR4 and DR5.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, SAHA substantially potentiated both AY4-and TRAIL-mediated cell death in K562 cells, while VPA had no such synergy. This difference between SAHA and VPA may be due to the fact that SAHA can inhibit all of four classes of HDACs while VPA can inhibit only Class I and IIa HDACs [16]. Different classes of HDACIs have also previously been found to induce diverged synergistic effects on TRAIL-induced apoptosis in K562 and Jurkat cells [27].…”

Section: Responses Of Various Leukemia Cell Lines To Ay4 or Trail Alonementioning

confidence: 99%

“…For example, subtoxic dosages of chemotherapeutic agents with different mechanisms of action, such as DNA damaging agents (doxorubicin and etoposide) [4,10,11], proteasome inhibitors (MG132) [12], phosphatidylinositol-3-kinase (PI3K)/Akt inhibitor (perifosine) [13], and NFjB pathway inhibitor (SN50) [14,15], potentiated TRAILmediated cell death in various types of leukemia cells by modulating the extrinsic or intrinsic pathways. In particular, histone deacetylase inhibitors (HDACIs) have shown extensive synergistic cell death-inducing activity in combination with TRAIL [3,16]. Valproic acid (VPA) significantly increased TRAIL-sensitivity of patient-derived primary chronic lymphocytic leukemia (CLL) cells by downregulating c-FLIP [17] and in an established chronic myeloid leukemia (CML) cell line by increasing expression of DR4 and DR5 [18].…”

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

et al. 2010

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Cell-death signaling through the pro-apoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, death receptor 4 (DR4) and DR5, has shown tumor-selective apoptotic activity. Here, we examine susceptibility of various leukemia cell lines (HL-60, U937, K562, CCRF-CEM, CEM-CM3, and THP-1) to an anti-DR4 agonistic monoclonal antibody (mAb), AY4, in comparison with TRAIL. While most of the leukemia cell lines were intrinsically resistant to AY4 or TRAIL alone, the two T-cell acute lymphoblastic leukemia (T-ALL) lines, CEM-CM3 and CCRF-CEM cells, underwent synergistic caspase-dependent apoptotic cell death by combination of AY4 or TRAIL with a histone deacetylase inhibitor (HDACI), either suberoylanilide hydroxamic acid (SAHA) or valproic acid (VPA). All of the combined treatments synergistically downregulated several antiapoptotic proteins (c-FLIP, Bcl-2, Bcl-X L , XIAP, and survivin) without significant changing the expression levels of pro-apoptotic proteins (Bax and Bak) or the receptors (DR4 and DR5). Downregulation of c-FLIP to activate caspase-8 was a critical step for the synergistic apoptosis through both extrinsic and intrinsic apoptotic pathways. Our results demonstrate that the HDACIs have synergistic effects on DR4-specific mAb AY4-mediated cell death in the T-ALL cells with comparable competence to those exerted by TRAIL, providing a new strategy for the targeted treatment of human T-ALL cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Responses Of Various Leukemia Cell Lines To Ay4 or Trail Alonementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

et al. 2010

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“…Finally, histone acetylation [50] and deacetylation [51] are known to be mechanisms that alter the transcriptional regulation of genes by changing their chromatin structure. With regard to the role of histone acetylation in apoptosis, Jüngel et al [52] exploited trichostatin A (TSA), a Streptomyces metabolite and inhibitor of mammalian histone acetylases [53], to show that TSA when combined with TRAIL led to an induction of RASF apoptosis, whereas either TSA or TRAIL alone sparingly induced apoptosis in these cells.…”

Section: Trailmentioning

confidence: 99%