Epigenetic therapy of lymphoma using histone deacetylase inhibitors

Cotto, Maribel; Cabanillas, Fernando; Tirado, Maribel; García, María Victoria; Pacheco, Eileen

doi:10.1007/s12094-010-0527-3

Cited by 32 publications

(26 citation statements)

References 59 publications

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“…3C). Consistent with earlier reports of other HDAC inhibitors (15,(19)(20)(21), we observed that CUDC-907 and panobinostat induced cell-cycle arrest at G 2 -M phase. In contrast, the PI3K inhibitors GDC-0941 and BEZ-235 predominantly induced G 0 /G 1 cell-cycle arrest ( Fig.…”

Section: Cudc-907 Induces Apoptosis and G 2 -M Cell-cycle Arrest In Csupporting

confidence: 93%

Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

Qian

Lai

Bao

et al. 2012

Clinical Cancer Research

201

176

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Purpose: Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells.Experimental Design: We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action.Results: CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells.Conclusions: CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks. Clin Cancer Res; 18(15); 4104-13. Ó2012 AACR.

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Section: Cudc-907 Induces Apoptosis and G 2 -M Cell-cycle Arrest In Csupporting

confidence: 93%

Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

Qian

Lai

Bao

et al. 2012

Clinical Cancer Research

201

176

View full text Add to dashboard Cite

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“…For instance, HDACi and DNMT inhibitors have been tested for the treatment of aggressive non-Hodgkin's Lymphomas (NHLs) [136][137][138][139][140][141][142][143][144][145].…”

Section: Hematological Malignanciesmentioning

confidence: 99%

“…This data provided the structural basis for the catalytic mechanism and the inhibition of this family of enzymes, paving the way for the design of new bioactive molecules able to interfere with the deacetylation reaction. Several compounds targeting HDACs entered clinical trials in the last year and have been reviewed elsewhere [98,105,139,141,234,237,[240][241][242][243]. These proteins belong to the open / folding class, with an eight-stranded parallel -sheet sandwiched between -helices.…”

Section: Class I Ii and Iv Deacetylasesmentioning

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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“…Class I, II, and IV HDACs require zinc for their enzymatic activity, whereas class III HDACs, also known as silent informant regulator proteins (sirtuins), require nicotinamide adenine dinucleotide (NAD + ) as a coenzyme for their activity. [8][9][10] HDAC inhibitors are a chemically broad group of molecules found to inhibit the activity of HDACs at a wide range of concentrations, from low nanomolar to high millimolar levels. To date, there are several HDAC inhibitors in development, with the focus on greater potency and improved tolerability.…”

Section: Hdac Inhibitorsmentioning

confidence: 99%

Peripheral T cell lymphoma: clinical utility of romidepsin

Zain¹,

Sawey²

2012

BLCTT

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Introduction: Direct therapeutic targets, such as aberrant tumor cell genes and tumor cell markers, have been the focus of cancer treatment for more than 50 years. The resulting damage to normal cells and emergence of drug-resistant tumor cells after exposure to conventional chemotherapy have led researchers to study indirect targets, like the tumor vasculature. A more recent indirect approach involves targeting the epigenetic modifiers, DNA methyltransferase and histone deacetylase. Histone deacetylase inhibitors have been shown to be active cytotoxic agents in T cell lymphoma. The current treatments approved by the US Food and Drug Administration for relapsed cutaneous T cell lymphoma are vorinostat and romidepsin. The diversity and rarity of peripheral T cell lymphomas present a challenge for effective treatment. With their poor overall survival rate, new targeted therapies need to be developed.

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Epigenetic therapy of lymphoma using histone deacetylase inhibitors

Cited by 32 publications

References 59 publications

Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling

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

Peripheral T cell lymphoma: clinical utility of romidepsin

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