The International Journal of Biochemistry & Cell Biology
ReviewEpi-drugs to fight cancer: From chemistry to cancer treatment, the road ahead
Introduction
A great research interest has been focused on the pharmacological restoration of epigenetic regulation balance by using epi-drugs. At the present, pharmaco-epigenomics constitute the hope for a new strategy in cancer treatment.
Nucleosomes are the basal units that structure the eukaryotic chromatin. A typical nucleosome is composed of an octamer of the four pairs of core histones H2A, H2B, H3 and H4, and ∼146 base pairs of DNA wrapped around them (Luger et al., 1997). The core histone N-terminal domains are rich in positively charged basic amino acids, which can actively interact with DNA (Lenfant et al., 1996). The chromatin barrier formed by histone–DNA interaction blocks the binding of the basic transcription complex to gene promoters, and suppresses gene expression (Gregory et al., 2001). The dynamic process of histone acetylation has been linked to gene transcription, and histone deacetylation has been related to inactive chromatin (Grunstein, 1997). Under physiological conditions, chromatin acetylation is regulated by the balanced action of histone acetyltransferases (HATs) and deacetylases (HDACs). The HATs transfer acetyl groups from acetyl coenzyme A (acetyl-CoA) onto the ɛ-amino groups of conserved lysine residues within the core histones (Tanner et al., 1999). Acetylation can neutralize the positive charge of histones, loosening their interactions with the negatively charged DNA backbone, and leading to a more “open” active chromatin structure that favours the binding of transcription factors for active gene transcription (Gregory et al., 2001). Contrarily, the re-establishment of the positive charge in the amino-terminal tails of core histones catalyzed by HDACs is thought to tighten the interaction between histones and DNA, blocking the binding sites on promoter thus inhibiting gene transcription. Obviously, a subtly orchestrated balance between the actions of HATs and HDACs is essential to the maintenance of normal cellular functions, and shifts of this balance in both senses might have dramatic consequences on the cell phenotypes such as carcinogenesis (Altucci et al., 2005, Minucci and Pelicci, 2006).
Another major epigenetic modification is the methylation of cytosine residues in genomic DNA (Bird, 2002). About 4% of the cytosines are typically methylated in genomic DNA and this methylation is essential in development (Li et al., 1992). DNA methylation plays an essential role in epigenetic phenomena, including genomic imprinting (Li et al., 1993), X-chromosome inactivation (Panning and Jaenisch, 1996), and retroelement silencing (Walsh et al., 1998). CpG dinucleotides represent the consensus target sequences of DNA methylation in differentiated mammalian cells, but only a relatively small fraction of these sequences becomes methylated. CpG dinucleotides can be clustered in CpG islands which are often related with promoter regions and stay unmethylated for most genes. The signals that determine whether a particular CpG island becomes methylated have not been determined yet, but protein–protein interactions between DNA methyltransferases and chromatin-associated proteins might play an central role (Burgers et al., 2002). As a consequence, DNA methylation is not uniformly distributed over the genome. While the majority of repetitive elements are deeply methylated, gene-specific methylation appears to be restricted. DNA methylation patterns can be altered in human tumors (Ehrlich, 2002). Tumor cells are characterized by specific genetic and epigenetic changes that promote uncontrolled cellular proliferation (Jones and Baylin, 2002, Jones and Baylin, 2007). DNA methylation is catalyzed by DNA methyltransferases, a family of enzymes that comprises DNMT1, DNMT2, DNMT3A and DNMT3B in human cells (Goll and Bestor, 2005). DNA methyltransferase knockouts effects on DNA methylation patterns have been analyzed by both 24 differential methylation hybridization and amplification of inter-methylated sites (Paz et al., 2003). Based on the rationale that hypermethylation-induced gene silencing could be uncovered by gene demethylation and reactivation, many efforts have been put in the identification and characterization of inhibitors of DNA methylation as tools to treat cancer.
This review will discuss the latest ‘epi-drug’ discoveries focusing on the chemical characterization and use of epigenetic modulators in pre-clinical and clinical settings against cancer.
Section snippets
Chemistry of HDAC inhibitors (HDACi) and anticancer applications
Over-expression or malfunction of HDACs may be a cause of carcinogenesis. Sequentially, deregulation of gene expression may induce cancer. HDAC inhibitors (HDACi) are thought to be able to interact with the catalytic domain of histone deacetylases to block the substrate recognition ability of these enzymes, thus resulting in restoration of relevant genes expression (Finnin et al., 1999, Finnin et al., 2001). The main biological effects of HDACi are cell cycle arrest, induction of
Chemistry of SIRT inhibitors and their applications against cancer
In contrast to class I/II/IV HDACi, the inhibitors of class III HDACs (sirtuins) are much less validated as anticancer agents and in general less developed on the pharmacological side. Sirtuins play an important role in many cellular processes such as gene silencing, regulation of transcription factors [i.e., the tumor suppressor and sequence-specific DNA-binding transcription factor p53, the p53-related p73, p300 histone acetyltransferase (HAT), E2F1, NF-κB, and others], fatty acid metabolism,
DNA methylation inhibition for the treatment of cancer
DNA methylation at the C5 position of cytosine in CpG nucleotides, catalyzed by DNMTs with the involvement of S-adenosyl-l-methionine as the methyl donor, is a physiological mechanism of epigenetic regulation of gene expression. However, hypermethylation of CpG islands leads to gene silencing and is known to be a common marker of cancer cells (Esteller, 2002). The first reported DNMT inhibitors (DNMTi) were two cytidine analogues, 5-aza- and 5-aza-2′-deoxycytidine (5-aza-CR and 5-aza-CdR) (
Inhibitors of acetyltransferases (HATs) against cancer
A large group of transcriptional regulators, mainly co-activators, exhibit intrinsic HAT activity. Among them, the p300/cAMP response element binding protein (CREB)-binding protein (CBP) family is involved in several cellular processes such as proliferation, differentiation, and apoptosis (Chan and La Thangue, 2001). Chromosomal translocation of the genes that encode p300 or CBP with those for other HAT proteins (such as monocytic leukemia zinc finger (MOZ) and MOZ-related factor (MORF)
Inhibitors of histone methylation
In addition to histone and non-histone protein acetylation, histone methylation has also been shown to be important in epigenetic regulation of gene expression through the establishment of stable gene-expression patterns. Differently from acetylation, histone methylation does not alter the overall charge of histone tails, but has an influence on basicity, hydrophobicity, and on the affinity for anionic molecules such as DNA. Histone methylation can occur on both Lys (K) or Arg (R) residues.
Inhibitors of demethylases
Two classes of histone demethylases have been described up to now, different in their reaction chemistry, coenzyme use, and reaction products. Lysine-specific histone demethylase 1 (LSD1) is a FAD-dependent enzyme that catalyzes the oxidative removal of one or two methyl groups from H3K4 or, when in complex with the androgen receptor, H3K9, releasing formaldehyde and hydrogen peroxide (Shi et al., 2004, Metzger et al., 2005). LSD1 takes part to a transcriptional repressor complex, with the
Perspectives, remarks and conclusions
The pharmacoepigenomic field is highly improved in the last years. Old drugs have been rediscovered for new functions and new molecules have been developed to target epigenetic enzymes and their alterations in cancer. We are just at the beginning of the understanding of the cross-talk between genetic information and epigenetic regulation. Whereas HDACi have entered the anticancer field with the application of SAHA to CTCL, all the other epi-drugs are still at the molecular or preclinical
Acknowledgements
Lucia Altucci dedicates this work to the memory of Lucia Latela, died fighting cancer and alive in the memory of those who love her.
Work in the author’s laboratories is supported by EU EPITRON LSHC-CT2005-518417; CANCERDIP 200620; APO-SYS 200767 (LA), PRIN 2006 (LA; AM), La Regione Campania L5 annualità 2005 (LA), AIRC 2007 (AM), FIRB RBIP067F9E and RETI FIRB RBPR05NWWC_006 (AM).
References (182)
- et al.
Acute myeloid leukemia: therapeutic impact of epigenetic drugs
Int J Biochem Cell Biol
(2005) - et al.
Hexamethylene bisacetamide in myelodysplastic syndrome and acute myelogenous leukemia: a phase II clinical trial with a differentiation-inducing agent
Blood
(1992) - et al.
Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression
J Biol Chem
(2004) - et al.
Small molecule modulators of histone acetyltransferase p300
J Biol Chem
(2003) - et al.
Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription
J Biol Chem
(2004) - et al.
Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors
J Biol Chem
(2005) - et al.
The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines
Blood
(2002) - et al.
Arginine methylation an emerging regulator of protein function
Mol Cell
(2005) - et al.
Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1
J Biol Chem
(2002) - et al.
The anticancer prodrugs of butyric acid AN-7 and AN-9, possess antiangiogenic properties
Cancer Lett
(2007)
DNA methyltransferases get connected to chromatin
Trends Genet
A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia
Blood
Structural insights into histone demethylation by JMJD2 family members
Cell
Small molecule regulators of protein arginine methyltransferases
J Biol Chem
Combined effects of novel tyrosine kinase inhibitor AMN107 and histone deacetylase inhibitor LBH589 against Bcr-Abl-expressing human leukemia cells
Blood
Histone acetylation and chromatin remodeling
Exp Cell Res
DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes
Semin Hematol
Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening
J Biol Chem
MLL: a histone methyltransferase disrupted in leukemia
Trends Mol Med
MS-275, a potent orally available inhibitor of histone deacetylases—the development of an anticancer agent
Int J Biochem Cell Biol
Chromatin control and cancer-drug discovery: realizing the promise
Drug Discov Today
Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress
Blood
The epigenomics of cancer
Cell
Cellular differentiation, cytidine analogs and DNA methylation
Cell
Decitabine dosing schedules
Semin Hematol
N-(3-(4-Hydroxyphenyl)-propenoyl)-amino acid tryptamides as SIRT2 inhibitors
Bioorg Med Chem Lett
Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase
Mol Cell
Potential anticancer activity of turmeric (Curcuma longa)
Cancer Lett
Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator
Cancer Cell
HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF
Mol Cell
Procainamide is a specific inhibitor of DNA methyltransferase 1
J Biol Chem
Targeted mutation of the DNA methyltransferase gene results in embryonic lethality
Cell
High-performance liquid chromatographic analysis of chemical stability of 5-aza-2′-deoxycytidine
J Pharm Sci
Anticancer potential of curcumin: preclinical and clinical studies
Anticancer Res
R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies
Br J Cancer
Gateways to clinical trials
Methods Find Exp Clin Pharmacol
Identification of a small molecule inhibitor of Sir2p
Proc Natl Acad Sci USA
Isolation, characterization, and properties of a labile hydrolysis product of the antitumor nucleoside, 5-azacytidine
J Med Chem
Acetylation inactivates the transcriptional repressor BCL6
Nat Genet
Design, synthesis, and biological evaluation of a small-molecule inhibitor of the histone acetyltransferase Gcn5
Angew Chem Int Ed Engl
DNA methylation patterns and epigenetic memory
Genes Dev
The Sir2 family of protein deacetylases
Annu Rev Biochem
Anticancer activities of histone deacetylase inhibitors
Nat Rev Drug Discov
Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors
Leukemia
Potent cytodifferentiating agents related to hexamethylenebisacetamide
Proc Natl Acad Sci USA
Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases
Cancer Res
A Phase I clinical and pharmacological evaluation of sodium phenylbutyrate on an 120-h infusion schedule
Clin Cancer Res
p300/CBP proteins: HATs for transcriptional bridges and scaffolds
J Cell Sci
A phase I and pharmacokinetic study of dihydro-5-azacytidine (NSC 264880)
Cancer Res
DNA methylation in cancer: too much, but also too little
Oncogene
Cited by (178)
Targeting emerging cancer hallmarks by transition metal complexes: Epigenetic reprogramming and epitherapies. Part II
2023, Coordination Chemistry ReviewsEpigenetic linkage of systemic lupus erythematosus and nutrition
2023, Nutrition Research ReviewsDNA methylation in stress and depression: from biomarker to therapeutics
2021, Acta Neuropsychiatrica