DNA Methyltransferase-1 Inhibitors as Epigenetic Therapy for Cancer

Singh, Vikram; Sharma, Prince; Capalash, Neena

doi:10.2174/15680096113139990077

Cited by 134 publications

(84 citation statements)

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“…Epimutations such as promoter DNA methylation have been extensively held responsible for silencing of several tumour suppressor genes [5]. PAX1 promoter region and intragenic region have been reported to be highly methylated across ovarian cancer [6], head and neck cancer [1] and oral squamous cell carcinoma [7].…”

Section: Introductionmentioning

confidence: 99%

Promoter methylation-independent reactivation of PAX1 by curcumin and resveratrol is mediated by UHRF1

Parashar

Capalash

2015

Clin Exp Med

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Paired box gene1 (PAX1) is essential for normal chordate development and has been recently characterised to be a tumour suppressor gene which is frequently hypermethylated in different cancer types. We investigated the reactivation of PAX1 using curcumin and resveratrol in HeLa, SiHa and Caski cell lines and role of hypermethylation in 39 CpG sites of PAX1 promoter from -6 to -286 region in regulating its expression. Curcumin in HeLa and SiHa cells and resveratrol in Caski cells caused significant (P < 0.01) reactivation of PAX1 expression as shown by qRT PCR, but reversal of promoter hypermethylation was not observed across the three cell lines. Interestingly, even positive control 5-aza-2'-deoxycytidine was not found to be effective to cause demethylation of CpG sites under consideration suggesting the promoter region to be resistant towards hypomethylating effects as shown by bisulphite sequencing. However, a striking correlation between PAX1 reactivation and Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) downregulation after treatment with curcumin and resveratrol in HeLa, SiHa and Caski cell lines was observed which was further confirmed after transient silencing of UHRF1 expression. PAX1 reexpression was also obtained in Caski and SiHa cell lines after treatment with sodium butyrate, a histone deacetylase inhibitor, suggesting that PAX1 reactivation by curcumin and resveratrol may be due to their effect on histone deacetylase mediated through downregulation of UHRF1 which can regulate both DNA methylation and histone acetylation.

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Section: Introductionmentioning

confidence: 99%

Promoter methylation-independent reactivation of PAX1 by curcumin and resveratrol is mediated by UHRF1

Parashar

Capalash

2015

Clin Exp Med

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“…Previous studies of histone deacetylase inhibitors and methyltransferase inhibitors have demonstrated that the anticancer potential of these drugs is mediated via the re-expression of tumor suppressor genes such as RUNX3 and ARHI (26,27). Recently, HDACs have been shown to play a role in modulating gene transcription and the proliferation and differentiation of a variety of cell types, thereby affecting the pathogenesis of certain diseases (28,29).…”

Section: Discussionmentioning

confidence: 99%

Breast cancer cells are arrested at different phases of the cell cycle following the re-expression of ARHI

et al. 2014

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Abstract. ARHI is a maternally imprinted tumor suppressor gene that is expressed in normal breast epithelial cells but not in most breast cancer cells. Aberrant methylation and hypernomic histone deacetylation have been implicated in the silencing of ARHI. To investigate the mechanism of ARHI induction, MDA-MB-231 breast cancer cells were either transfected with the eukaryotic expression vector, pcDNA3.1(+)-ARHI, or were simultaneously treated with a histone deacetylase inhibitor, [trichostatin A, (TSA)] and the methyltransferase inhibitor, 5-aza-2'-deoxycytidine (DAC). The latter treatment group also included the targeting of ARHI by small interfering RNA (siRNA) to further examine interactions between ARHI and the drugs applied. Levels of ARHI were detected by western blotting, MTT assays were used to evaluate cell proliferation, and both cell cycle progression and apoptosis were detected using flow cytometry. Both the transfection of pcDNA3.1(+)-ARHI and the application of TSA+DAC induced the expression of ARHI. Furthermore, reduced cell proliferation, cell cycle arrest and enhanced apoptosis were observed for both groups compared to controls. However, a G1/S cell cycle arrest was observed for the pcDNA3.1(+)-ARHI group, while a G2 cell cycle arrest was observed for the TSA+DAC group. The latter effect was reversed with the introduction of ARHI-targeted siRNA in combination with TSA+DAC treatment. To further clarify these observations, expression levels of several key cell cycle regulators were analyzed by western blotting. The pcDNA3.1(+)-ARHI group exhibited higher expression levels of p53, p21 and p27, and lower levels of cyclin D1, CDK4 and CDK6 when compared to the control group (P<0.05). For the TSA+DAC group, higher levels of p53, p21, cyclin B1 and Chk1 were detected, concomitant with lower levels of CDK1, when compared to the control group. Taken together, these results suggest that ARHI acts as a tumor suppressor gene in MDA-MB-231 cells and, although TSA+DAC can block the cells at different cell cycle phage, the antitumor effect is ARHI-dependent.

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“…Cytosine analogues, 5-azacytidine (azacytidine, AZA, Vidaza®) and 5-aza-2'-deoxycytidine (decitabine, DAC, Dacogen®) have been established as efficient therapeutics for the treatment of blood malignancies, especially myelodysplastic syndrome [1][2][3] . They have two mechanisms of action: at low doses, they inhibit the expression of de novo DNA methyltransferases (DNMTs), and reactivate the tumor suppressor genes silenced by aberrant DNA methylation.…”

Section: Introductionmentioning

confidence: 99%

“…They have two mechanisms of action: at low doses, they inhibit the expression of de novo DNA methyltransferases (DNMTs), and reactivate the tumor suppressor genes silenced by aberrant DNA methylation. This determines the therapeutic efficacy of the drugs [1][2][3] . However, at high doses, they directly incorporate into nucleic acids resulting in impaired DNA and RNA synthesis, inhibition of protein production, and cell death.…”

Section: Introductionmentioning

confidence: 99%

Biodegradable system for drug delivery of hydrolytically labile azanucleoside drugs

Hrubý¹,

Agrawal²,

Policianova³

et al. 2016

BIOMED PAP

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Background. The archetypal DNA methyltransferase inhibitors, 5-azacytidine (AZA) and 5-aza-2'-deoxycytidine (DAC) are potent antineoplastic agents used in the treatment of mainly, blood malignancies. However, the administration of these drugs is confounded by their hydrolytic lability which decreases plasma circulation time. Here, we describe a new biodegradable, polyanhydride formulation for drug delivery that circumvents this drawback. Methods. Injectable/implantable polymeric microbeads containing dispersed microcrystals of hydrophilic AZA or DAC packed in a dry environment are protected from hydrolysis, until the hydrolytic zone reaches the core. Diclofenac is embedded into the formulation to decrease any local inflammation. The efficacy of the formulations was confirmed by monitoring the induced demethylation, and cytostatic/cytotoxic effects of continuous drug release from the timecourse dissolution of the microbeads, using an in vitro developed cell based reporter system. Results. Poly(sebaccic acid-co-1,4-cyclohexanedicarboxylic acid) containing 30 wt. % drug showed zero-order release (R 2 = 0.984 for linear regression), and release rate of 10.0 %/h within the first 5 h, and subsequent slower release of the remaining drug, thus maintaining the level of drugs in the outer environment considerably longer than the typical plasma half-life of free azanucleosides. At lower concentrations, the differences between powder drug formulations and microbeads were very low or negligible, however, at higher concentrations, we discovered equivalent or increasing effects of the drugs loaded in microbeads. Conclusions. The study provides evidence that microbead formulations of the hydrolytically labile azanucleoside drugs could prevent their chemical decomposition in aqueous solution, and effectively increase plasma circulation time.

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DNA Methyltransferase-1 Inhibitors as Epigenetic Therapy for Cancer

Cited by 134 publications

References 0 publications

Promoter methylation-independent reactivation of PAX1 by curcumin and resveratrol is mediated by UHRF1

Promoter methylation-independent reactivation of PAX1 by curcumin and resveratrol is mediated by UHRF1

Breast cancer cells are arrested at different phases of the cell cycle following the re-expression of ARHI

Biodegradable system for drug delivery of hydrolytically labile azanucleoside drugs

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