Epigenetic opportunities and challenges in cancer

doi:10.1016/j.drudis.2009.10.010

Drug Discovery Today

Volume 15, Issues 1–2, January 2010, Pages 65-70

https://doi.org/10.1016/j.drudis.2009.10.010 Get rights and content

Epigenetic covalent modifications of DNA and chromatin proteins strongly affect gene expression and cellular activity, and epigenetic misregulation occurs in several diseases, especially cancer. First-generation drugs targeting the relatively promiscuous DNA methylation and histone acetylation modifiers have had successes in the treatment of haematological cancers. Second-generation drug programmes are in the discovery phase, targeting epigenetic enzymes with more tightly defined modes of action. This review highlights some of the challenges in identifying the most appropriate new targets and the issues that need to be addressed to facilitate the successful entry of second-generation epigenetic drugs into the clinic.

Section snippets

Epigenetics and cancer

There is an extraordinary degree of complexity in chromatin modifications and signalling, yet there is substantial enthusiasm for the development and implementation of epigenetic therapies in several human disease areas, especially oncology. What has led to these high expectations? Broadly, it is a combination of three factors: axiom, experience and prediction.

Second-generation cancer epitherapeutics – the challenges

As shown in Fig. 3, DNMT and HDAC inhibitors are already licensed for certain indications, but programmes targeting the enzymes that perform the more subtle chromatin modifications are all in the discovery phase. This is an inevitable consequence of the pace at which epigenetic targets have been identified: DNMTs were being extracted from mammalian livers by the early 1970s [46], yet LSD1, the first enzyme shown to demethylate methylated histones, was only identified in 2004 [38]. The rapid

Concluding remarks

Epigenetic control of gene regulation is a rapidly developing field of substantial potential, and oncology is likely to be the therapeutic application in which the fastest progress is made. However, if knowledge, know-how and clinical expertise remain in isolated silos, as is currently the case, epigenetic therapies will continue to reach the market but in an ad hoc and inefficient manner, which will fail to meet fully the needs of industry or patients. A more co-ordinated approach, involving

Acknowledgements

The authors thank Neil Pegg and David Knowles for helpful discussions.

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The subtle balance between acetylation and deacetylation of the histone proteins has a significant influence on chromatin compactness and gene expression. Histone deacetylation, which is catalyzed by histone deacetylases (HDACs), results in chromatin condensation and transcription silencing [145,146]. If these processes occur in cancer-transformed cells, they confer to the cells the ability to evade apoptosis and loss of proliferation control.
Cancer is one of the leading causes of death worldwide. This review highlights the importance of metal-catalyzed azide–alkyne cycloaddition reactions in the synthesis of ferrocenyl-x-1,2,3-triazolyl-R (x = none or a linker and R = organic entity) compounds with anticancer activity. First, information on metal-catalyzed azide–alkyne reactions and cancer chemotherapy was provided, followed by a concise introduction to ferrocenes as anticancer agents. Then the synthesis of ferrocenyl-x-1,2,3-triazolyl-R compounds using metal-catalyzed azide–alkyne cycloaddition reactions and their anticancer activity were discussed. More than 160 ferrocenyl-triazoles (282 compounds in total) were discussed in this review, which were divided into four classes: N-alkylaminoferrocenes, drugs and enzyme inhibitors, natural product conjugates, and other systems. The discussed ferrocenes were tested against lymphoma, lung, colon and colorectal, breast, prostate, ovarian, hepatocellular and ductal, pancreatic, and glioblastoma cancer cells. From the observations of this review, it can be concluded that among metal-catalyzed azide–alkyne cycloaddition reactions, different variants of copper-catalyzed azide–alkyne cycloaddition reactions play an important role as they yield the highest number of ferrocenyl-x-1,2,3-triazolyl compounds with anticancer activity. In the majority of the cases, the 1,2,3-triazolyl entity served only as a linking group, but in some compounds, it also played a key role in anticancer activity. Oxidative stress and reactive oxygen species generation are the most common ways in which the ferrocenyl moiety contributes to the anticancer activity of 1,2,3-triazolyl derivatives. This review has 23 figures and 24 schemes, and 208 references were cited.
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Histone deacetylase inhibitors with desirable pharmacokinetic profiles which can be delivered to solid tumor tissues in large amount might be promising to treat solid tumor effectively. Herein, structural modification of a previously reported tetrahydroisoquinoline-based HDAC inhibitor 1 was carried out to improve its plasma stability for more feasible drug delivery. Among three newly synthesized analogs, the in vitro rat plasma stability of compound 2 (t_1/2 = 630 min) was over 5-fold improved than its parent 1 (t_1/2 = 103 min). In vitro activity evaluation showed that compound 2 and 1 exhibited similar HDACs inhibitory activity, which was validated by western blot analysis and antiproliferative assay. Moreover, compared with 1, compound 2 exhibited comparable, if not higher, in vivo antitumor activity in a human breast carcinoma (MDA-MB-231) xenograft model.
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It has been evident that dysregulation of epigenetic modification is involved in genesis, progression, heterogeneity and acquired drug resistance of cancers [44,45]. Currently, the major epigenetic therapies for cancer applied in clinical practice involve inhibition of DNA methyltransferase (DNMT) and HDACs [1]. Mammalian HDACs are grouped into four classes based on their structural homology to their yeast homologues.
Epigenetic mutations are closely associated with human diseases, especially cancers. Among them, dysregulations of histone deacetylases (HDACs) are commonly observed in human cancers. Recent years, HDAC inhibitors have been identified as promising anticancer agents; several HDAC inhibitors have been applied in clinical practice. In this study, we synthesized a novel N-hydroxyacrylamide-derived HDAC inhibitor, I-7ab, and examined its antitumor activity. Our investigations demonstrated that I-7ab exerted cytotoxicity toward and inhibited the growth of human cancer cell lines at micromolar concentrations. Among tested cells, HCT116 was the most sensitive one to the treatment of I-7ab. However, I-7ab displayed far less cytotoxicity in human normal cells. In HCT116 cells, I-7ab inhibited the expression of class I HDACs, especially that of HDAC3, and suppressed EGFR signaling pathway. With respect to the cytotoxic effect of I-7ab, it induced apoptosis via increasing the Bax/Bcl-2 ratio and suppressing the translocation of NF-κB. Other than inducing apoptosis, I-7ab inhibited the expression of cyclin B1 and thereby arrests cell cycle progression at G2/M phase. Further analyses revealed potential role of p53 and p21 in I-7ab-induced apoptosis and cell cycle arrest. According to our findings, I-7ab may serve as a lead compound for potential antitumor drugs.
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In this direction, different studies have highlighted how the histone alterations contribute to the onset and growth of a variety of cancers [7,23,24,27,32–41], among other pathologies. Consequently, enzymes operating PTMs on histones are constituting attractive therapeutic targets for the development of new therapies [13,31,42–44]. It should be noted that, while the resulting effects on chromatin collectively depend on the ensemble of histone PTMs, these are operated by precise variations of physicochemical properties that we recently reviewed [17].
Growing evidences show that epigenetic mechanisms play crucial roles in the genesis and progression of many physiopathological processes. As a result, research in epigenetic grew at a fast pace in the last decade. In particular, the study of histone post-translational modifications encountered an extraordinary progression and many modifications have been characterized and associated to fundamental biological processes and pathological conditions. Histone modifications are the catalytic result of a large set of enzyme families that operate covalent modifications on specific residues at the histone tails. Taken together, these modifications elicit a complex and concerted processing that greatly contribute to the chromatin remodeling and may drive different pathological conditions, especially cancer. For this reason, several epigenetic targets are currently under validation for drug discovery purposes and different academic and industrial programs have been already launched to produce the first pre-clinical and clinical outcomes. In this scenario, computer-aided molecular design techniques are offering important tools, mainly as a consequence of the increasing structural information available for these targets. In this mini-review we will briefly discuss the most common types of known histone modifications and the corresponding operating enzymes by emphasizing the computer-aided molecular design approaches that can be of use to speed-up the efforts to generate new pharmaceutically relevant compounds.
Physicochemical modifications of histones and their impact on epigenomics
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As a consequence of the increasing interest in this topic, many recent articles and reviews have reported and described new types of modification, specific histone residues that undergo PTMs and enzymes that operate these modifications [17–20]. In addition, many other studies have elucidated the impact that PTMs have on chromatin and on the recruitment of chromatin regulators, as well as their clinicopathological relevance in human disease [8,10,18,21–29]. A further level of knowledge stems from the observation that the selectivity of histone PTMs varies depending on the kind of modification: for example, acetylation is the most promiscuous histone modification, and is always associated with transcriptional activity; by contrast, methylation has a high degree of selectivity and is associated with repression or transcription, depending on the methylated residue and the number of attached methyl groups [30,31].
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Section snippets

Epigenetics and cancer

Second-generation cancer epitherapeutics – the challenges

Concluding remarks

Acknowledgements

Mutat. Res.

Cell

Cell

Cell

Cell

Mutat. Res.

J. Biol. Chem.

Gynecol. Oncol.

J. Thorac. Oncol.

Cell

Blood

Mol. Cell

J. Biol. Chem.

Am. J. Hum. Genet.

Mol. Cell

An operational definition of epigenetics

Genes Dev.

Targeting aberrant chromatin structure in colorectal carcinomas

Cancer J.

How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers

Nat. Struct. Mol. Biol.

Inactivation of the HIV LTR by DNA CpG methylation: evidence for a role in latency

EMBO J.

DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: evidence for multistep maintenance of mammalian X dosage compensation

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

Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation

Science

Studies of X chromosome DNA methylation in normal human cells

Nature

PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing

Nat. Struct. Mol. Biol.

Activation of chromatin by acetylation of histone side chains

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

Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins

Nature

The genomic landscape of histone modifications in human T cells

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

Deciphering the combinatorial histone code

Nat. Methods

Modifications of the histone N-terminal domains. Evidence for an “epigenetic code”?

Mol. Biotechnol.

Translating the histone code

Science

Histone acetylation and an epigenetic code

Bioessays

Review
Post Screen
Epigenetic opportunities and challenges in cancer