DNMT1: An emerging target in the treatment of invasive urinary bladder cancer

Dhawan, Deepika; Ramos‐Vara, José A.; Hahn, Noah M.; Waddell, Jolena N.; Olbricht, Gayla R.; Zheng, Rong; Stewart, Janet; Knapp, Deborah W.

doi:10.1016/j.urolonc.2012.03.015

Cited by 38 publications

(28 citation statements)

References 39 publications

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“…The expression of estrogen and androgen receptors has also been reported in canine InvUC [19]. In addition, in microarray studies (canine normal bladder, canine InvUC, and human microarray data—GEO database), there were >400 genes differentially expressed between normal and tumor in both dogs and humans [71, 73]. …”

Section: Naturally Occurring Canine Invasive Bladder Cancer and Rementioning

confidence: 99%

“…Aberrant DNA methylation has been identified in multiple genes in human InvUC [107, 108]. DNA methyltransferase 1 (DNMT1), which is a key player in the aberrant methylation process, has been noted to be overexpressed in human and canine InvUC [73, 109]. When considering the design of clinical trials of demethylating agents in humans, key valuable information that could be rapidly obtained from dogs includes efficacy, safety, and treatment scheduling.…”

Section: Examples Of Targeted Therapy Research Utilizing the Caninmentioning

confidence: 99%

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Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs

Fulkerson

Dhawan

Ratliff

et al. 2017

International Journal of Genomics

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Genomic analyses are defining numerous new targets for cancer therapy. Therapies aimed at specific genetic and epigenetic targets in cancer cells as well as expanded development of immunotherapies are placing increased demands on animal models. Traditional experimental models do not possess the collective features (cancer heterogeneity, molecular complexity, invasion, metastasis, and immune cell response) critical to predict success or failure of emerging therapies in humans. There is growing evidence, however, that dogs with specific forms of naturally occurring cancer can serve as highly relevant animal models to complement traditional models. Invasive urinary bladder cancer (invasive urothelial carcinoma (InvUC)) in dogs, for example, closely mimics the cancer in humans in pathology, molecular features, biological behavior including sites and frequency of distant metastasis, and response to chemotherapy. Genomic analyses are defining further intriguing similarities between InvUC in dogs and that in humans. Multiple canine clinical trials have been completed, and others are in progress with the aim of translating important findings into humans to increase the success rate of human trials, as well as helping pet dogs. Examples of successful targeted therapy studies and the challenges to be met to fully utilize naturally occurring dog models of cancer will be reviewed.

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Section: Naturally Occurring Canine Invasive Bladder Cancer and Rementioning

confidence: 99%

Section: Examples Of Targeted Therapy Research Utilizing the Caninmentioning

confidence: 99%

Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs

Fulkerson

Dhawan

Ratliff

et al. 2017

International Journal of Genomics

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“…The inhibition of DNMTs activity has been presented as a possible pathway to reactivate genes silenced by methylation of their promoters in different diseases, including cancer [1,12,18]. The relationship between the hypermethylation of promoter of tumor suppressor genes and cancer development has been clearly demonstrated [3,4,19], suggesting DNMTs as promising drug targets for the discovery of new and more potent/selective anticancer drugs [20].…”

Section: Figure 1 May Go Herementioning

confidence: 99%

“…The selection criteria for NPs was a Total score value greater than 6.0 (-log(Kd)) for both M a n u s c r i p t 12 DNMT structures used, selecting the best 19 NPs as promising DNMTis, as observed in Table 3, which also show affinity values obtained with AutoDock Vina for these compounds. …”

Section: Figure 3 May Go Herementioning

confidence: 99%

“…1) [6][7][8][9] . Currently, three types of cytosine-5 DNMTs have been identified, including two de novo DNA methyltransferases; DNMT3A and DNMT3B, which establish the methylation patterns during embryonic development in mammals and in differentiated cells [10,11]; and DNMT1, the most abundant and active of these enzymes responsible for copying the methylation pattern of DNA during cell division [12,13]. It has been shown that DNMT1 plays an important role in carcinogenesis [12,14], therefore, these targets are of particular interest to search for specific inhibitors [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

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Computational fishing of new DNA methyltransferase inhibitors from natural products

Maldonado-Rojas

Olívero-Verbel

Marrero-Ponce

2015

Journal of Molecular Graphics and Modelling

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Chronic exposure to ethanol of male mice before mating produces attention deficit hyperactivity disorder‐like phenotype along with epigenetic dysregulation of dopamine transporter expression in mouse offspring

Kim

Choi

Park

et al. 2014

J of Neuroscience Research

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Preconception exposure to EtOH through the paternal route may affect neurobehavioral and developmental features of offspring. This study investigates the effects of paternal exposure to EtOH before conception on the hyperactivity, inattention, and impulsivity behavior of male offspring in mice. Sire mice were treated with EtOH in a concentration range approximating human binge drinking (0-4 g/kg/day EtOH) for 7 weeks and mated with untreated females mice to produce offspring. EtOH exposure to sire mice induced attention deficit hyperactivity disorder (ADHD)-like hyperactive, inattentive, and impulsive behaviors in offspring. As a mechanistic link, both protein and mRNA expression of dopamine transporter (DAT), a key determinant of ADHD-like phenotypes in experimental animals and humans, were significantly decreased by paternal EtOH exposure in cerebral cortex and striatum of offspring mice along with increased methylation of a CpG region of the DAT gene promoter. The increase in methylation of DAT gene promoter was also observed in the sperm of sire mice, suggesting germline changes in the epigenetic methylation signature of DAT gene by EtOH exposure. In addition, the expression of two key regulators of methylation-dependent epigenetic regulation of functional gene expression, namely, MeCP2 and DNMT1, was markedly decreased in offspring cortex and striatum sired by EtOH-exposed mice. These results suggest that preconceptional exposure to EtOH through the paternal route induces behavioral changes in offspring, possibly via epigenetic changes in gene expression, which is essential for the regulation of ADHD-like behaviors.

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DNMT1: An emerging target in the treatment of invasive urinary bladder cancer

Cited by 38 publications

References 39 publications

Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs

Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs

Computational fishing of new DNA methyltransferase inhibitors from natural products

Chronic exposure to ethanol of male mice before mating produces attention deficit hyperactivity disorder‐like phenotype along with epigenetic dysregulation of dopamine transporter expression in mouse offspring

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