Chromatin modifying agents – the cutting edge of anticancer therapy

doi:10.1016/j.drudis.2011.05.012

Drug Discovery Today

Volume 16, Issues 13–14, July 2011, Pages 543-547

https://doi.org/10.1016/j.drudis.2011.05.012 Get rights and content

Chromatin modifying compounds are emerging as the next generation of anticancer therapies. By altering gene expression they could be able to correct uncontrolled proliferation and, in certain cases, aberrant apoptotic pathways, which are hallmarks of malignant cells. The modulation of gene expression is regulated via chromatin remodelling processes that include DNA methylation and chromatin modifications. The identification of aberrant methylation of genes and dysregulated histone acetylation status in cancer cells provides a basis for novel epigenetic therapies. Currently available chromatin modifying agents, a group that includes DNA methyltransferase and histone deacetylase inhibitors, exert anticancer effects by reactivating tumour suppressor genes, inhibiting proliferation and inducing apoptosis. It is anticipated that massive parallel sequencing will identify new epigenetic targets for drug development.

Introduction

DNA methylation and histone acetylation are epigenetic processes that play a major part in the regulation of genes that control vital cellular processes such as proliferation, survival and differentiation [1]. The balance in the activity of DNA methyltransferases (DNMTs), DNA demethylases, histone acetyltransferases (HATs) and histone deacetylases (HDACs) is crucial in mediating these epigenetic processes. An imbalance in the activity of these enzymes could result in hypermethylation of tumour suppressor genes, global genomic hypomethylation and gene silencing via histone deacetylation in cancer cells, suggesting an important role for abnormal chromatin metabolism in tumourigenesis 1, 2.

Epigenetic changes, in contrast to genetic modifications, are typically reversible, creating a unique target for therapeutic strategies in cancer. DNMT and HDAC inhibitors can reactivate epigenetically silenced tumour suppressor genes and decrease tumour cell growth in vitro and in vivo [3]. For example, overexpression of HDAC1, 2, 5, 7 and 8, and an increased expression of DNMT1, 3A and 3B, have been reported in various solid tumours, including lung, gastric and breast cancers, compared with normal tissue [3]. These epigenetic abnormalities provide the basis for the development of chromatin modifying compounds as anticancer therapeutics. However, despite numerous investigational chromatin modifying agents currently in preclinical or clinical trials, only four epigenetic-based drugs have been approved by the FDA to date. These are the DNMT inhibitors (DNMTIs) 5-azacytidine (Vidaza^®) and 5-aza-2′-deoxycytidine (Decitabine^®); and the HDAC inhibitors (HDACIs) suberoylanilide hydroxamic acid (SAHA; vorinostat; Zolinza^®) and romidepsin (depsipeptide; Istodax^®) [1]. Here, we provide an overview of the FDA-approved epigenome-targeting compounds and other novel chromatin modifying agents (DNMTIs and HDACIs) as antineoplastic agents (Fig. 1). In addition, the controversies surrounding these types of therapies and potential future directions in the field will be addressed.

Section snippets

DNA methyltransferase inhibitors

The inactivation of DNMT activity reduces DNA methylation and has been shown to correct the abnormal hypermethylation of selected genes, such as tumour suppressor genes including p53, RIZ1 and glutathione-S-transferase π, in malignant cells; thereby restoring the activation of the genes [4]. Further, by inhibiting DNMTs, reactivation of genes encoding immunological molecules such as human leukocyte antigen (HLA) class I molecules has also been shown to restore immunorecognition of tumour cells

Histone deacetylase inhibitors

Inhibitors of HDAC activity are classified as a group of novel chromatin modifying agents. Common examples of HDACIs include Zolinza^®, Istodax^®, valproic acid and trichostatin A (Table 2) [22]. HDACIs generally contain a polar terminal moiety, which binds a zinc ion of the HDAC catalytic pocket. The ability of HDACIs to interfere with chromatin remodelling processes results in the accumulation of hyperacetylated histones. This, in turn, inhibits transcriptional activation of many genes; some of

Controversies surrounding DNMT and HDAC inhibitors

Although current FDA-approved and emerging DNMTIs and HDACIs have shown promise as antitumour therapeutics, success in clinical trials has been limited to haematological malignancies with inconsistent efficacy against solid tumours 24, 29. The reduced efficacy of chromatin modifying agents in solid tumours compared with haematological malignancies could be because only actively proliferating cells permit the incorporation of these drugs into the DNA [29]. As mentioned earlier, a concern with

Concluding remarks

Chromatin modifying agents have emerged as a new generation of anticancer therapeutic with clinical success, particularly in haematological malignancies. Inhibitors of DNMT and HDAC enzymes have been the primary focus of epigenetic-based treatments for various malignancies. It is expected that these compounds will be most effective when used in combination with conventional chemotherapy and radiotherapy. In this context, an important issue is the appropriate selection of optimal drug

Conflicts of interest

The authors of this Feature article have no conflicts of interest to declare.

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PerspectiveFeatureChromatin modifying agents – the cutting edge of anticancer therapy

Introduction

Section snippets

DNA methyltransferase inhibitors

Histone deacetylase inhibitors

Controversies surrounding DNMT and HDAC inhibitors

Concluding remarks

Conflicts of interest

Mol. Cell

Blood

Epigenetic therapy: histone acetylation, DNA methylation and anti-cancer drug discovery

Curr. Cancer Drug Targets

DNA methylation and cancer

J. Clin. Oncol.

Differential expression of histone modifier genes in human solid cancers

BMC Genomics

S110, a 5-aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth

Mol. Cancer Ther.

Hypermethylation of HLA class I gene is associated with HLA class I down-regulation in human gastric cancer

Tissue Antigens

Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines

Cancer Res.

DNA methylation of developmental genes in pediatric medulloblastomas identified by denaturation analysis of methylation differences

Proc. Natl. Acad. Sci. U. S. A.

Angiostatic activity of DNA methyltransferase inhibitors

Mol. Cancer Ther.

Azacitidine: a novel drug for myelodysplastic syndrome

Indian J. Pharmacol.

Randomised controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B

J. Clin. Oncol.

Clinical advances in hypomethylating agents targeting epigenetic pathways

Curr. Cancer Drug Targets

Identification of hypermethylated genes associated with cisplatin resistance in human cancers

Cancer Res.

Long-term stability of demethylation after transient exposure to 5-aza-2′-deoxycytidine correlates with sustained RNA polymerase II occupancy

Mol. Cancer Res.

Perspective
Feature
Chromatin modifying agents – the cutting edge of anticancer therapy