Epigenetic cancer therapy: rationales, targets and drugs

Abstract

The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. Over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. The results showed that both established drug classes, the histone deacetylase (HDAC) inhibitors and the DNA methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. HDAC inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. Similarly, the induction of global DNA demethylation by non-specific inhibition of DNA methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. Second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. As such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. Recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. Druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity.

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

“…Smallmolecule inhibitors of histone deacetylases (HDACs), histone acetyltransferases (HATs), histone lysine methyltransferases (KMTs) and protein arginine methyltransferases (PRMTs) are already in clinical use or in the drug development pipeline [1,95]. Given the importance of epigenetics in oncogenic transformation, many of these molecules are aimed at treating tumours [26,96].…”

“…Other well-known epigenetic therapeutics are inhibitors of DNA methylation like the nucleoside analogues 5-aza-CR and 5-aza-CdR [95]. These compounds have been approved by the FDA as treatments for leukemia and myelodysplastic miR-29b [80] Promote cell differentiation in muscle and tumours miR-7 [81] syndromes [103].…”

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

“…+39 051 2094004; Fax: +39 051 2094746; Email: alberto.delrio@gmail.com # These authors contributed equally to this work and regulation of the immune system [29,30], epigenetic changes are at the limelight of cancer research. Many studies have found that alterations in the epigenetic code may contribute to the onset of growth and progression of a variety of cancers [20,21,23,[31][32][33][34][35][36][37][38][39][40][41]. For this reason, these enzymes are attractive therapeutic targets for the development of new cancer therapies [3,[42][43][44][45].…”

“…These covalent modifications are able to cause other PTMs and the ensemble of this cross-talk is known as the histone code, which can be positively or negatively correlated with specific transcriptional states or organization of chromatin [11,[18][19][20]. The fine regulation of histone PTMs and DNA methylation is controlled and catalyzed by many different classes of enzymes whose existence and functions have been elucidated with an extraordinary progression in the last decade [12,[20][21][22][23][24][25]. Epigenetic modifications are reversible nuclear chemical reactions that are due to enzymes able to exercise opposing catalytic effects [5,20].…”

Reprogramming and Carcinogenesis—Parallels and Distinctions

“…Growing body of evidence collected mainly in the last three decades show important role of epigenetic changes in carcinogenesis, and cancer progression (Hellebrekers et al, 2007;Rius and Lyko, 2012). Low resolution scanning of genomes of ES-cells IPS cells and cancer cells revealed largely overlapping but not identical pattern of DNA methylation (Doi et al, 2009).…”