Targeting the DNA Damage Response in Cancer

Ljungman, Mats

doi:10.1021/cr900047g

Cited by 141 publications

(103 citation statements)

References 631 publications

(890 reference statements)

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“…+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].…”

Section: Introductionmentioning

confidence: 99%

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

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

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Abstract:Research on cancer epigenetics has flourished in the last decade. Nevertheless growing evidence point on the importance to understand the mechanisms by which epigenetic changes regulate the genesis and progression of cancer growth. Several epigenetic targets have been discovered and are currently under validation for new anticancer therapies. Drug discovery approaches aiming to target these epigenetic enzymes with small-molecules inhibitors have produced the first pre-clinical and clinical outcomes and many other compounds are now entering the pipeline as new candidate epidrugs. The most studied targets can be ascribed to histone deacetylases and DNA methyltransferases, although several other classes of enzymes are able to operate post-translational modifications to histone tails are also likely to represent new frontiers for therapeutic interventions. By acknowledging that the field of cancer epigenetics is evolving with an impressive rate of new findings, with this review we aim to provide a current overview of pre-clinical applications of smallmolecules for cancer pathologies, combining them with the current knowledge of epigenetic targets in terms of available structural data and drug design perspectives.Keywords: Epigenetics, anticancer therapy, DNA methyltransferases, protein methyltransferases, demethylases, deacetylases, acetyltransferases, histone post-translational modifications, drug design, crystallography, small-molecule inhibitors. INTRODUCTIONThe term epigenetics currently refers to the mechanisms of temporal and spatial control of gene activity that do not depend on the DNA sequence, influencing the physiological and pathological development of an organism. The molecular mechanisms by which epigenetic changes occur are complex and cover a wide range of processes including paramutation, bookmarking, imprinting, gene silencing, carcinogenesis progression, and, most importantly, regulation of heterochromatin and histone modifications [1]. At a biochemical level, epigenetic alterations in chromatin involve methylation of DNA patterns, several forms of histone modifications and microRNA (miRNA) expression. All these processes modulate the structure of chromatin leading to the activation or silencing of gene expression [2][3][4][5][6]. More specifically, the chromatin remodeling is accomplished by two main mechanisms that concern the methylation of cytosine residues in DNA and a variety of post-translational modifications (PTMs) occurring at the N-terminal tails of histone proteins. These PTMs include acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, glycosylation, ADPribosylation, carbonylation, citrullination and biotinylation [7,8]. Among all PTMs for example, histone tails can have its lysine residues acetylated, methylated or ubiquitilated; arginine can be methylated; serine and threonine residues can be phosphorylated [9][10][11][12][13][14][15][16][17]. These covalent modifications are able to cause other PTMs and the ensemble of this cross-talk is known as the his...

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Section: Introductionmentioning

confidence: 99%

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

Andreoli¹,

Barbosa²,

Parenti³

et al. 2012

CPD

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“…In general, this prediction has been confirmed 65 . However, therapeutic agents that directly inhibit these critical proteins are still years from reaching clinical trial.…”

Section: Strategies For Sensitizationmentioning

confidence: 64%

“…Clinical trial success has led to FDA-approval for treatment of NSCLC. Several studies have demonstrated that EGFR inhibition sensitized tumor cells to radiation 65 . Insights into the mechanism underlying this sensitization have been provided by several recent studies.…”

Section: Epidermal Growth Factor Receptor (Egfr) Inhibitorsmentioning

confidence: 99%

“…Finally, CDK1 inhibition causes the loss of a critical phosphorylation event on BRCA1 required for its HR function 91 . There are additional modulators of DDR and DNA repair not described here 65 . Indeed, the number of pharmacologic inhibitors that either directly or indirectly inhibit DSB repair is being uncovered at a rapid pace.…”

Section: Other Late Stage Clinical Trial Agentsmentioning

confidence: 99%

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DNA Damage Response and Repair: Insights into Strategies for Radiation Sensitization

Lawson¹,

Kahle²,

Ng³

et al. 2011

Selected Topics in DNA Repair

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“…In addition they have potent antimalarial activity (Yeats et al, 2008) and good anticonvulsant activity against acutely elicited Seizures (Revas et al, 2009). On the other hand curcumin is a principal curcuminoid of Indian curry and has known for its antitumor (Ran et al, 2009;Wohlmuth et al, 2010;Ljngman, 2009), antioxidant, anti-inflammatory (Takahashi et al, 2009;Kuhad et al, 2007;Michaelidou and H-Litina, 2005) and antiarthritic properties (Patil et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Antiviral and Quantitative Structure Activity Relationship Study for Dihydropyridones Derived from Curcumin

Saeed¹,

Saour²,

Elias³

et al. 2010

American J. of Immunology

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Targeting the DNA Damage Response in Cancer

Cited by 141 publications

References 631 publications

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

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

DNA Damage Response and Repair: Insights into Strategies for Radiation Sensitization

Antiviral and Quantitative Structure Activity Relationship Study for Dihydropyridones Derived from Curcumin

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