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: 2.48). 02/2011; 7(2):263-83. DOI: 10.2217/fon.11.2
Source: PubMed


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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    • "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.
    Full-text · Article · Jan 2015 · Neuropharmacology
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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.
    Full-text · Article · Aug 2014 · Cancer Letters
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    • "Moreover, inhibitors of IMPDH are accredited with significant ability of differentiation and apoptosis (Dun et al., 2013). On the other hand, SAHA (Suberoylanilide hydroxamic acid) (Gupta et al.) is the HDAC inhibitor that has been recently approved for the cutaneous T cell lymphoma treatment (Rangwala et al., 2012; Tan et al., 2010; Thurn et al., 2011). SAHA brings about alteration in gene transcription in addition to exerting antitumor effects as a consequence of apoptosis, differentiation, and inhibition of tumor angiogenesis (Marks, 2010). "
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    ABSTRACT: Past few decades have witnessed the dawn of new diseases in which cancer is a major problem and the race ensued to eradicate cancer by charting out various effective therapeutic regimens. Circumventing resistance issues and combating the toxicity and selectivity problems are matter-of-concern in cancer treatment. Persistent fail- ure to ensure complete remission and eradication of cancer instigated the researchers to exploit the strategies of com- bining pharmacophores as targeted therapeutic agents. Momentous improvement in the pharmacokinetic as well as pharmacodynamic profile resulting in the enhancement of bioavailability was seen with the introduction of these pharmacophores. The scope of molecular hybridization can be clearly exemplified through the US-FDA approved estramustine and others such as CUDC-101, CBLC-137, PLX3397, E-3810, and CUDC-907 that are currently in different phases of clinical trials. This review seeks to highlight and discuss anti-proliferative activity of some important hybrid, dual, and multi-targeted pharmacophores reported to date along with their designs, structure activity relationships, scope, and limitations. Further, an emphasis has been made to summarize US-FDA approved as well as drugs currently undergoing clinical trials of anticancer drug development.
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