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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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    • "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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    • "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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