Thurn KT, Thomas S, Moore A, Munster PNRational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer. Future Oncol 2: 263-283

Department of Medicine, Hematology/Oncology Division. University of California-San Francisco, 1600 Divisadero Street, San Francisco, CA 94115, USA.
Future Oncology (Impact Factor: 2.61). 02/2011; 7(2):263-83. DOI: 10.2217/fon.11.2
Source: PubMed

ABSTRACT Histone deacetylases (HDACs) regulate the acetylation of a variety of histone and nonhistone proteins, controlling the transcription and regulation of genes involved in cell cycle control, proliferation, survival, DNA repair and differentiation. Unsurprisingly, HDAC expression is frequently altered in hematologic and solid tumor malignancies. Two HDAC inhibitors (vorinostat and romidepsin) have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. As single agents, treatment with HDAC inhibitors has demonstrated limited clinical benefit for patients with solid tumors, prompting the investigation of novel treatment combinations with other cancer therapeutics. In this article, the rationales and clinical progress of several combinations with HDAC inhibitors are presented, including DNA-damaging chemotherapeutic agents, radiotherapy, hormonal therapies, DNA methyltransferase inhibitors and various small-molecule inhibitors. The future application of HDAC inhibitors as a treatment for cancer is discussed, examining current hurdles to overcome before realizing the potential of this new approach.

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Available from: Scott Thomas, Aug 25, 2015
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    • "It is possible that excessive levels of histone acetylation may shift the acetylation/deacetylation balance towards toxic levels, thereby providing a possible explanation for the apparently discrepant observation that HDAC inhibitors are protective in the ischemic brain but toxic in preconditioned brain tissue. This is not surprising if we take into account that HDAC inhibitors induce apoptosis in tumoral cells (Emanuele et al., 2008; Jazirehi, 2010) and are currently being tested in clinical trials for anticancer therapy (Lane and Chabner, 2009; Thurn et al., 2011). Along this view, we herein show that HDAC inhibitors prevent the reduction of Bcl-2 induced by OGD and, in a model of focal ischemia in vivo, we have previously shown that HDAC inhibitors at high doses lose their ability to increase the expression of neuroprotective genes (Faraco et al., 2006). "
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    ABSTRACT: Ischemic tolerance is an endogenous defense program in which exposure to a subtoxic preconditioning insult results in resistance to a subsequent, otherwise lethal, episode of ischemia. Herein, we evaluated the role of histone acetylation/deacetylation in an in vitro model of preconditioning, using rat organotypic hippocampal slices exposed to 30 min oxygen-glucose deprivation (OGD), which leads to CA1 injury 24 h later: tolerance was induced by exposing the slices to preconditioning bouts of NMDA (3 μM for 60 min) 24 h prior to the toxic OGD challenge. Under these conditions, CA1 damage induced by OGD was reduced. The induction of tolerance was prevented by incubating the slices with HDAC inhibitors. NMDA preconditioning was associated with a mild increase in poly(ADP-ribose) polymerase (PARP) activity that was apparently followed, 3 h later, by a mild increase in histone acetylation. Use of PARP and HDAC inhibitors suggests a possible interaction between PARP and HDAC activities in the development of ischemic tolerance. Finally, both PARP and HDAC inhibitors were able to prevent the increase in pERK1/2 induced by NMDA preconditioning. We propose a model in which mild histone acetylation and PARP activity cooperate in producing a neuroprotective response in the development of ischemic tolerance. Copyright © 2015. Published by Elsevier Ltd.
    Neuropharmacology 01/2015; 92. DOI:10.1016/j.neuropharm.2015.01.008 · 4.82 Impact Factor
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    • "Multiple clinical trials, either with HDACIs alone or in combination with other agents are currently underway. They are used in a wide range of hematologic malignancies and many different solid tumors [63] [68] [69]. The most frequently used HDACIs in open clinical studies comprise vorinostat (n = 57), panobinostat (n = 41), romidepsin (n = 23), valproic acid (in cancer: n = 22), entinostat (n = 9) and belinostat (n = 6) (; March 2014). "
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    ABSTRACT: Endometrial stromal sarcoma (ESS) and undifferentiated endometrial sarcoma (UES) are very rare gynecologic malignancies. Due to the rarity and heterogeneity of these tumors, little is known about their epidemiology, pathogenesis, and molecular pathology. Our previous studies have described deregulation of histone deacetylases expression in ESS/UES samples. Some of these enzymes can be inhibited by substances which are already approved for treatment of cutaneous T-cell lymphoma. On the basis of published data, they may also provide a therapeutic option for ESS/UES patients. Our review focuses on molecular mechanisms of ESS/UES. It describes various aspects with special emphasis on alteration of histone deacetylation and its possible relevance for novel therapies.
    Cancer Letters 08/2014; 354(1). DOI:10.1016/j.canlet.2014.08.013 · 5.62 Impact Factor
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    • "Consistent with this consideration, the expression of VEGFR2 itself was reported to decrease in response to long-term treatment with KDACi (Deroanne et al., 2002; Kwon et al., 2002). In this respect, a challenging issue would be to understand at what extent the acetylation-dependent upregulated activity of VEGFR2 might be responsible for the relatively poor efficacy of KDACi monotherapy, which is rescued by the combination with a VEGFR tyrosine kinase inhibitor (Qian et al., 2004; Thurn et al., 2011; Qiu et al., 2013). Taken together, our findings support the conclusion that VEGFR2 acetylation favors and sustains receptor activation in endothelial cells, and reinforces the concept that a strict crosstalk exists between PTM by acetylation and other PTMs (Yang and Seto, 2008a). "
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    ABSTRACT: The tyrosine kinase receptor vascular endothelial growth factor receptor 2 (VEGFR2) is a key regulator of angiogenesis. Here we show that VEGFR2 is acetylated in endothelial cells both at four lysine residues forming a dense cluster in the kinase insert domain and at a single lysine located in the receptor activation loop. These modifications are under dynamic control of the acetyltransferase p300 and two deacetylases HDAC5 and HDAC6. We demonstrate that VEGFR2 acetylation essentially regulates receptor phosphorylation. In particular, VEGFR2 acetylation significantly alters the kinetics of receptor phosphorylation after ligand binding, allowing receptor phosphorylation and intracellular signaling upon prolonged stimulation with VEGF. Molecular dynamics simulations indicate that acetylation of the lysine in the activation loop contributes to the transition to an open active state, in which tyrosine phosphorylation is favored by better exposure of the kinase target residues. These findings indicate that post-translational modification by acetylation is a critical mechanism that directly affects VEGFR2 function.
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