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Review
. 2011:2011:514261.
doi: 10.1155/2011/514261. Epub 2011 Jun 28.

Therapeutic strategies to enhance the anticancer efficacy of histone deacetylase inhibitors

Claudia P Miller  1 , Melissa M Singh, Nilsa Rivera-Del Valle, Christa A Manton, Joya Chandra
Affiliations
Review

Therapeutic strategies to enhance the anticancer efficacy of histone deacetylase inhibitors

Claudia P Miller et al. J Biomed Biotechnol. 2011.

Abstract

Histone acetylation is a posttranslational modification that plays a role in regulating gene expression. More recently, other nonhistone proteins have been identified to be acetylated which can regulate their function, stability, localization, or interaction with other molecules. Modulating acetylation with histone deacetylase inhibitors (HDACi) has been validated to have anticancer effects in preclinical and clinical cancer models. This has led to development and approval of the first HDACi, vorinostat, for the treatment of cutaneous T cell lymphoma. However, to date, targeting acetylation with HDACi as a monotherapy has shown modest activity against other cancers. To improve their efficacy, HDACi have been paired with other antitumor agents. Here, we discuss several combination therapies, highlighting various epigenetic drugs, ROS-generating agents, proteasome inhibitors, and DNA-damaging compounds that together may provide a therapeutic advantage over single-agent strategies.

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Figures

Figure 1
Figure 1
Proposed mechanisms by which HDACi induce ROS. (a) Mitochondrial injury. HDACi induces expression of Bid protein. This proapoptotic molecule binds to and disrupts the mitochondrial membrane, which results in increased ROS levels and apoptosis. (b) Alterations in antioxidant levels. HDACi upregulate the expression of thioredoxin-binding protein-2 (TBP-2). TBP-2 binds to and inhibits the antioxidant thioredoxin (Trx). This inhibition results in an imbalance of oxidants and antioxidants leading to increased ROS levels, which promotes apoptosis.
Figure 2
Figure 2
Activation of apoptosis by combinations of HDACi and ROS-generating agents. HDACi combined with agents like adaphostin and PEITC result in an increase production of ROS in cancer cells. The high levels of ROS result in induction of apoptosis via caspase activation.
Figure 3
Figure 3
Combination of HDACi with proteasome inhibitors induces cellular stress. Synergistic apoptosis is observed between HDACi and three structurally different proteasome inhibitors—marizomib, carfilzomib, and bortezomib. The cell death observed with this therapeutic strategy is generally oxidant dependent. Individually both proteasome inhibitors and HDACi generate ROS, either via mitochondrial injury or by disregulating antioxidant systems as described in the text. When paired, these two compounds dramatically increase oxidative stress, which leads to apoptosis. High levels of ROS can also cause damage to proteins which can contribute to ER stress. Inhibiting the proteasome also results in aggregates of conjugated ubiquitin proteins that were originally to be degraded by the proteolytic complex. HDAC 6 mediates aggresome formation as a cytoprotective measure in the cell. Addition of HDACi disrupts aggresomes, leading to ER stress, which can stimulate oxidative stress or directly induce apoptosis.
Figure 4
Figure 4
Several therapeutic combinations with HDACi show promising results. Some agents which have been shown to cause synergistic cell death when combined with HDACi include (1) DNA-damaging agents, such as radiation and many chemotherapies, which may take advantage of the increased access to DNA, provided by the “loose” chromatin arrangement after HDACi treatment, to cause increased DNA damage, (2) modulators of methylation, such as histone demethylase inhibitors and DNA methyltransferase inhibitors, which have been shown to contribute changes to the methylome that act synergistically with the actions of HDACi, (3) proteasome inhibitors, which increase cellular stress and lead to production of reactive oxygen species, can synergize with HDACi, and (4) ROS-generating agents, such as adaphostin, work with HDACi to amplify ROS production, adding to the already increased ROS levels in cancer cells until toxic levels lead to cell death.
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