2′-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine: A novel inhibitor of DNA methyltransferase that requires activation by human carboxylesterase 1

Byun, Hyang‐Min; Choi, Si Ho; Laird, Peter W.; Trinh, B.; Siddiqui, M. Arshad; Márquez, Víctor E.; Yang, Allen S.

doi:10.1016/j.canlet.2008.02.069

Cited by 44 publications

(25 citation statements)

References 37 publications

(43 reference statements)

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“…RX-3117 has been approved by the FDA for the treatment of pancreatic cancers. In addition, more nucleoside analogues were designed and studied for their ability to inhibit DNMTs, such as 2-(p-nitrophenyl) ethoxycarbonyl-DAC (NPEOC-DAC), CP-4200, 4'-thio-2'-deoxycytidine (TdCyd), and 5-aza-4'-thio-2'-deoxycytidine (5-aza-T-dCyd) (Patent Numbers WO2009042766, WO2009042767, WO2011109012 and US 20110218170 A1) (Byun et al, 2008;Brueckner et al, 2010;Thottassery et al, 2010;Thottassery et al, 2014) (Table 3). Collectively, these findings suggest we are close to finding low toxicity DNMT-depleting anticancer drugs.…”

Section: Nucleosidic Dna Methylation Inhibitorsmentioning

confidence: 99%

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Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Liu

Lau

et al. 2015

Pharmacology & Therapeutics

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Section: Nucleosidic Dna Methylation Inhibitorsmentioning

confidence: 99%

“…NPEOC-DAC 18499340 (Byun et al, 2008) SGI-110 20442312 (Chuang et al, 2010) CP-4200 20442313 (Brueckner et al, 2010) (Fahy et al, 2009) …”

mentioning

confidence: 98%

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Liu

Lau

et al. 2015

Pharmacology & Therapeutics

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“…Because of its dependency on metabolism by carboxylesterase for biologic activity, NPEOC-decitabine can be specifically used to target cancer cells with high expression of carboxylesterase, while other tissues with low levels of the enzyme will not be affected. [115,152] Unfortunately, high levels of carboxylesterase are only observed in hepatic carcinomas, thus restricting the potential of this drug in clinical use to this malignancy. An additional limitation of NPEOC-decitabine is its very low solubility in water, which severely limits its bioavailability.…”

Section: Specific Targetingmentioning

confidence: 98%

“…[115] NPEOC-decitabine requires activation by human carboxylesterase for biologic activity. In the presence of carboxylesterase 1 (CES1), the N4 nitrophenyl group on NPEOC-decitabine is cleaved, resulting in decitabine, which can then be incorporated into the DNA sequence.…”

Section: Specific Targetingmentioning

confidence: 99%

The Application of Delivery Systems for DNA Methyltransferase Inhibitors

Lim

Neilsen²,

Kumar³

et al. 2011

BioDrugs

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DNA methylation, which often occurs at the cytosine residue of cytosine-guanine dinucleotides, is critical for the control of gene expression and mitotic inheritance in eukaryotes. DNA methylation silences gene expression either by directly hindering the access of transcription factors to the target DNA, or through recruitment of histone deacetylases to remodel the chromatin structure to an inactive state. Aberrant hypermethylation of tumor suppressor genes is commonly associated with the development of cancer. A number of anti-cancer agents have been developed that function through demethylation, reversing regional hypermethylation to restore the expression of tumor suppressor genes. Azacitidine and decitabine are used in the clinic, but their applications are limited to myelodysplastic syndrome and other blood-related diseases. Despite the potency of these drugs, their broader clinical application is restricted by cytotoxicity, nonspecific targeting, structural instability, catabolism, and poor bioavailability. Further improvements in the delivery systems for these drugs could overcome the issues associated with inefficient bioavailability, whilst facilitating the administration of combinations of demethylating agents and histone deacetylase inhibitors to enhance efficacy. This review focuses on the current limitations of existing demethylating agents and highlights possible approaches using recent developments in drug delivery systems to improve the clinical potential of these drugs.

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“…151 In vitro studies have demonstrated the ability to cleave this NPEOC group by carboxylesterase enzymes resulting in the production of decitabine. The compound has demonstrated molecular changes in human cancer cell lines as evidenced by decreased global and gene specific methylation, however, this effect was limited to cells expressing carboxylesterase 1.…”

Section: Other Demethylating Agentsmentioning

confidence: 99%

DNA Methylation: Its Role in Cancer Development and Therapy

Kurkjian¹,

Kummar²,

Murgo³

2008

Current Problems in Cancer

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Inflammation and Methylation ChangesChanges in the genome which result in cancer promotion remain a complex interplay of aberrant methylation in the setting of a multitude of epigenetic changes. The events leading to these disruptions in methylation have been postulated; though remain to be fully elucidated. A causal relationship between inflammation and cancer has long been accepted in multiple tumor types, most prominently colon cancer; an association supported by the evidence that non-steroidal anti-inflammatory medications can potentially stop the development of colon cancer. Investigations in patients with ulcerative colitis who have a predisposition to the development of colon cancer have established a potential link between inflammation and cancer by the demonstration of hypermethylated gene promoters in early dysplastic lesions. 1 The mechanisms responsible for the contribution of inflammation to cancer remain to be fully understood. Mutagenesis resulting from the production of halogenated nucleotide precursors in activated neutrophils and eosinophils with subsequent incorporation into DNA has been demonstrated in vitro. 2,3 The link between inflammation-induced halogenated nucleotides and aberrant methylation stems from the demonstration that methyl-binding proteins cannot distinguish between methylated cytosine residues and chlorinated or brominated cytosine nucleotides. Furthermore, DNMT1 also could not distinguish between 5-methylcytosine and some 5-halocytosine products which could potentially result in mistaken methylation at sites of inflammation. 4 These halogenated cytosine residues were not recognized by DNA repair enzymes suggesting the possibility of accumulation of heritable changes within the genome.Infection with Helicobacter pylori has been implicated in the development of gastric cancer with a relative risk increase of 2.2-to 6 fold when infection is detected. 5-8 The mechanism of cancer development in this setting has been attributed to inflammation leading to cell proliferation resulting in a propensity for gene mutation. Aberrant methylation due to H. pylori infection has been suggested as an additional mechanism bridging the gap between inflammation and cancer. In a series of 154 healthy volunteers and 72 patients with gastric cancer, methylation of 8 regions of 7 CpG islands was assessed. 14 Among the healthy volunteers, the extent of DNA methylation was 5.4-to 303-times higher in the H. pylori positive cases compared to the H. pylori negative cases (p<0.0001) suggesting an increase in methylation levels due to the presence of H. pylori. However, the comparison of methylation levels between healthy volunteers and patients with gastric cancer stratified by H. pylori status

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2′-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine: A novel inhibitor of DNA methyltransferase that requires activation by human carboxylesterase 1

Cited by 44 publications

References 37 publications

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation

The Application of Delivery Systems for DNA Methyltransferase Inhibitors

DNA Methylation: Its Role in Cancer Development and Therapy

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