The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy

Ellis, Leigh; Bots, Michael; Lindemann, Ralph K.; Bolden, Jessica E.; Newbold, Andrea; Cluse, Leonie A.; Scott, Clare L.; Strasser, Andreas; Atadja, Peter; Lowe, Scott W.; Johnstone, Ricky W.

doi:10.1182/blood-2008-10-182758

Cited by 109 publications

(126 citation statements)

References 54 publications

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“…5-7 is of high clinical significance. Several HDAC inhibitors have already proven to have efficacy in mouse models of Myc-induced lymphoma (38,39), but the molecular mechanism is not fully understood. The model put forward here correctly predicts that only induced genes would be shared between HDAC inhibitor and BET inhibitor transcriptional output.…”

Section: Discussionmentioning

confidence: 99%

“…When white blood cell counts had increased above those of healthy mice, we treated mice with the Food and Drug Administration (FDA)-approved HDAC inhibitor vorinostat, RVX2135, or both in combination. Previous studies in lymphoma-bearing mice had shown monotherapy efficacy of HDAC inhibitors including vorinostat, but we used a much lower concentration, 40 mg·kg −1 ·d −1 , instead of 100-200 mg·kg −1 ·d −1 (38,39). RVX2135 and the combination treatment efficiently reduced the leukocytosis in just a few days, whereas vorinostat did not (Fig.…”

Section: Beti Induce Genes and Biological Effects Reminiscent Of Histonementioning

confidence: 99%

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BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Bhadury

Nilsson

Muralidharan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

195

147

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The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myctransgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell-cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.T he bromodomain and extraterminal (BET) domain family of proteins Brd2, Brd3, Brd4, and BrdT bind via their tandem bromodomains (BD1 and BD2) to acetylated lysines in histones and other proteins (1). On binding, they regulate the transcription of genes critical for cell-cycle progression and apoptosis. Therefore, BET proteins have emerged as interesting proteins for targeted intervention of cancer.Recently, the small-molecule BET inhibitor (+)-JQ-1 (hereafter JQ1) was found to be a potent and specific suppressor of B cell-lineage malignancies (2, 3). In acute myelogenous leukemia, BRD4 is essential for tumor maintenance, and JQ1 recapitulates the effects of RNA interference of BRD4 (4, 5). JQ1 was subsequently shown to have an antiproliferative effect in other hematological malignancies and solid organ tumors including glioblastoma, prostate cancer, and neuroblastoma (6-10). The current model of how BET inhibitors (BETi) inhibit tumor cell proliferation places inhibition of MYC as mediating activity in lymphoid tumors, with Myc-independent activity in some solid tumor types such as lung adenocarcinoma (11). However, it has not been clear in hematopoietic tumor types whether the antiproliferative effects of BETi are mediated by suppression of MYC expression or whether effects on MYC are a correlative bystander of the mechanism, perhaps useful as a biomarker but not necessarily mechanistic (12).We have assessed the effect of RVX2135, a novel and orally bioavailable selective inhibitor of Brd2, Brd3, Brd4, and BrdT, in in vitro and in vivo models of Myc-induced lymphoma. We find that the effects are mediated by broad transcriptional changes and that these are genetically and functionally linked to histone deacetylase inhibitors. Results RVX2135 Blocks Proliferation of Myc-Induced Mouse Lymphoma Cellsand Induces Caspase-Dependent Apoptosis. RVX2135 is a novel small-molecule BET bromodoma...

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Section: Discussionmentioning

confidence: 99%

Section: Beti Induce Genes and Biological Effects Reminiscent Of Histonementioning

confidence: 99%

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Bhadury

Nilsson

Muralidharan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

195

147

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“…Autophagy may delay the onset of apoptosis during SAHA treatment through various mechanisms including clearance of reactive oxygen species that are generated during SAHA treatment (24), clearance of p62-containing protein aggregates, which may accumulate during HDAC inhibition, and clearance of damaged mitochondria (25).…”

Section: Discussionmentioning

confidence: 99%

Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death

Gammoh

Lam

Puente

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

191

175

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Autophagy is a cellular catabolic pathway by which long-lived proteins and damaged organelles are targeted for degradation. Activation of autophagy enhances cellular tolerance to various stresses. Recent studies indicate that a class of anticancer agents, histone deacetylase (HDAC) inhibitors, can induce autophagy. One of the HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA), is currently being used for treating cutaneous T-cell lymphoma and under clinical trials for multiple other cancer types, including glioblastoma. Here, we show that SAHA increases the expression of the autophagic factor LC3, and inhibits the nutrient-sensing kinase mammalian target of rapamycin (mTOR). The inactivation of mTOR results in the dephosphorylation, and thus activation, of the autophagic protein kinase ULK1, which is essential for autophagy activation during SAHA treatment. Furthermore, we show that the inhibition of autophagy by RNAi in glioblastoma cells results in an increase in SAHA-induced apoptosis. Importantly, when apoptosis is pharmacologically blocked, SAHA-induced nonapoptotic cell death can also be potentiated by autophagy inhibition. Overall, our findings indicate that SAHA activates autophagy via inhibiting mTOR and up-regulating LC3 expression; autophagy functions as a prosurvival mechanism to mitigate SAHA-induced apoptotic and nonapoptotic cell death, suggesting that targeting autophagy might improve the therapeutic effects of SAHA. transcription | ATG7 | necrosis H istone deacetylase (HDAC) inhibitors emerge as a new class of therapeutic agents with promising outcomes during the treatment of a wide range of cancer types (1). Hematological malignancies appear to be particularly sensitive to HDAC inhibitors; however, a number of additional cancer types are currently being tested for their response to HDAC inhibition therapy. For an example, suberoylanilide hydroxamic acid (SAHA, vorinostat), which inhibits HDACs 1, 2, 3, and 6, has been approved for treatment against cutaneous T-cell lymphoma and also has modest effects as a single agent on cancers of the prostate, ovaries, breast, colorectal, and glioblastoma (2, 3). Although their precise mode of action remains uncertain, a number of recent data suggest that HDAC inhibitors may induce apoptotic cell death through both chromatin-dependent and -independent mechanisms.Treatment with HDAC inhibitors most frequently induces apoptosis via the programmed activation of a series of proteases, called caspases (4-6). More recently, HDAC inhibition has been also shown to induce autophagy (7,8). Unlike apoptosis, the contribution of autophagy to cell death remains controversial and, most likely, context-dependent. Autophagy is a catabolic process by which cytosolic material is targeted for lysosomal degradation by means of double-membrane cytosolic vesicles, termed autophagosomes (9). The formation of autophagosomes is orchestrated by upstream signaling molecules, including the ULK1 and PI3K complexes, which signal to downstream complexes involved in the nucleation and...

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“…Two phases I clinical trials showed promising results using LBH-589 in an oral and intravenous form against CTCL (ref. 88 ) and leukemias, respectively 89 . Both studies found increased acetylation of histones in tumor cells that was associated with apoptosis.…”

Section: Clinical Studies and Registered Drugsmentioning

confidence: 99%

Histone deacetylase inhibitors in cancer therapy. A review

Hraběta¹,

Stiborová²,

Adam³

et al. 2014

BIOMED PAP

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a Background. Despite recent success toward discovery of more effective anticancer drugs, chemoresistance remains a major cause of treatment failure. There is emerging evidence that epigenetics plays a key role in the development of the resistance. Epigenetic regulators such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) play an important role in gene expression. The latter are found to be commonly linked with many types of cancers and influence cancer development. Overall, histone acetylation is being investigated as a therapeutic target because of its importance in regulating gene expression. This review summarizes mechanisms of the anticancer effects of histone deacetylase (HDAC) inhibitors and the results of clinical studies. Results. Different HDAC inhibitors induce cancer cell death by different mechanisms that include changes in gene expression and alteration of both histone and non-histone proteins. Enhanced histone acetylation in tumors results in modification of expression of genes involved in cell signaling. Inhibition of HDACs causes changed expression in 2-10 % of genes involved in important biological processes. The results of experiments and clinical studies demonstrate that combination of HDAC inhibitors with some anticancer drugs have synergistic or additive effects. Conclusions. Even though many biological effects of HDAC inhibitors have been found, most of the mechanisms of their action remain unclear. In addition, their use in combination with other drugs and the combination regime need to be investigated. The discovery of predictive factors is also necessary. Finally, a key question is whether the pan-HDAC inhibitors or the selective inhibitors will be more efficient for different types of cancers.

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The histone deacetylase inhibitors LAQ824 and LBH589 do not require death receptor signaling or a functional apoptosome to mediate tumor cell death or therapeutic efficacy

Cited by 109 publications

References 54 publications

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death

Histone deacetylase inhibitors in cancer therapy. A review

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