Therapeutic Strategies to Enhance the Anticancer Efficacy of Histone Deacetylase Inhibitors

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.

Histone deacetylase inhibitors in cancer therapy. A review

“…Co-treatment of prostate, pancreatic tumor, acute myelogenous leukemia (AML) AML1/ETO-positive and non small cell lung cancer (NSCLC) cells with trichostatin A and decitabine synergistically induced apoptosis 63,64,67,68 . In addition, an inhibitor of histone demethylases (tranylcypromine) and vorinostat showed synergistic enhancement of apoptosis in glioblastoma cells 45 .…”

“…HDAC inhibitors induce apoptosis in tumor cells by regulation of expression of proapoptotic and antiapoptotic genes 45 . Mechanisms by which different HDAC inhibitors induce apoptosis include activation of both extrinsic and intrinsic apoptotic pathways.…”

“…HDAC inhibitors have been demonstrated to influence death receptors and their ligands 46 . HDAC inhibitor-induced apoptosis has also been demonstrated to be associated with activation of the intrinsic pathway 45 . It can be concluded that in tumor cells exposed to HDAC inhibitors proapoptotic genes involved in the extrinsic and intrinsic apoptotic pathways are up-regulated, while expression of antiapoptotic genes is reduced 12 .…”

Present and Future Application of Nanoparticle Based Therapies in B-Chronic Lymphocytic Leukemia (B-CLL)

“…Several agents are also beginning to be tested in combination therapies, either as chemo-sensitizing agents in association with standard chemotherapy drugs or in combination with DNA methyltransferase inhibitors (DNMTi) in the context of the so-called "epigenetic therapies", aimed to revert epigenetic alterations found in cancer cells. Vorinostat has demostrated also efficacy in Hodgkin and Non-Hodgkin Lymphomas (53)(54)(55)(56). However, to date, targeting acetylation with HDACi as a monotherapy has shown modest activity against other cancers including B-CLL.…”

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

“…Combination strategies often are used with the rationale to epigenetically "prime" the cancer cells by treatment with epigenetically active agents to the activity of the subsequently administered second agent. 2 DNA methylation usually occurs by transfer of a methyl group to the cytosine of a cytosine-guanine dinucleotide (CpG), e.g., of gene promoters. This allows the binding of different proteins that ultimately prohibit the RNA polymerase to access this area and can therefore silence the respective gene.…”