Re-emerging Antimetabolites with Novel Mechanism of Action with Respect to Epigenetic Regulation: Basic Aspects

Sarkisjan, Dzjemma; Steenbergen, Renske D.M.; Cloos, Jacqueline; Peters, Godefridus J.

doi:10.1007/978-981-10-3332-2_18

Cited by 5 publications

(7 citation statements)

References 106 publications

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“…21 However, another explanation for the difference in expression might be related to a different ubiquitination and subsequent protein degradation. 22,23 The latter might also explain the lack of correlation between protein and mRNA expression. Alternative splicing might play a role as well as mentioned above.…”

Section: Discussionmentioning

confidence: 99%

“…Some small difference were observed, especially for DNMT3A and DNMT3B, but the overall global methylation was not different either. 14 Several novel anticancer drugs have been developed to target DNMTs, 23 with the aim to directly inhibit tumour growth or to modulate DNA methylation to enhance the efficacy of other drugs. For RX-3117 it was recently demonstrated that it is not only incorporated into RNA and DNA, but it can also inhibit DNMT1.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors.

Honeywell

Sarkisjan

Kristensen

et al. 2018

Nucleosides, Nucleotides and Nucleic Acids

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors.

Honeywell

Sarkisjan

Kristensen

et al. 2018

Nucleosides, Nucleotides and Nucleic Acids

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“…Inhibition of DNMT1 has been demonstrated in different cancer cell lines and was related to their sensitivity to the drug. DNMT1 is crucial for maintenance methylation [30]. Different RX-3117 concentrations were needed in various cell lines to reach the same level of DNMT1 suppression.…”

Section: Effect On Dna Methyltransferasementioning

confidence: 99%

“…The mechanism of DNMT1 downregulation seems to be related to an increased protein breakdown. Normally DNMT1 acts on the DNA during the so-called base flipping for methyl transfer [30]. Treatment of the NSCLC cell line A549 and the pancreatic cancer cell line SUIT-028 with RX-3117 demonstrated trapping of DNMT1 to DNA.…”

Section: Effect On Dna Methyltransferasementioning

confidence: 99%

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

Balboni

Hassouni

Honeywell

et al. 2019

Expert Opinion on Investigational Drugs

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Introduction: RX-3117 is an oral, small molecule cytidine analog anticancer agent with an improved pharmacological profile relative to gemcitabine and other nucleoside analogs. The agent has excellent activity against various cancer cell lines and xenografts including gemcitabine-resistant variants and it has excellent oral bioavailability; it is not a substrate for the degradation enzyme cytidine deaminase. RX-3117 is being evaluated at a daily oral schedule of 700 mg (5 days/week for 3 weeks) which results in plasma levels in the micromolar range that have been shown to be cytotoxic to cancer cells. It has shown clinical activity in refractory bladder cancer and pancreatic cancer. Areas covered: The review provides an overview of the relevant market and describes the mechanism of action, main pharmacokinetic/pharmacodynamic features and clinical development of this investigational small molecule. Expert opinion: RX-3117 is selectively activated by uridine-cytidine kinase 2 (UCK2), which is expressed only in tumors and has a dual mechanism of action: DNA damage and inhibition of DNA methyltransferase 1 (DNMT1). Because of its tumor selective activation, novel mechanism of action, excellent oral bioavailability and candidate biomarkers for patient selection, RX-3117 has the potential to replace gemcitabine in the treatment of a spectrum of cancer types.

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“…RX-3117 is a novel cytidine analog modified in the sugar ring moiety [1] (Figure 1), which has shown promising anti-tumor activity against gemcitabine resistant xenografts from different pathologies [2] and is currently in clinical trial (NCT02030067) [3]. RX-3117 was shown to down-regulate DNA methyl transferase 1 (DNMT1) [1,[3][4][5][6]. The pharmacological consequences of this inhibition, however, have not been identified.…”

Section: Introductionmentioning

confidence: 99%

RX-3117 (Fluorocyclopentenyl-Cytosine)-Mediated Down-Regulation of DNA Methyltransferase 1 Leads to Protein Expression of Tumor-Suppressor Genes and Increased Functionality of the Proton-Coupled Folate Carrier

Sarkisjan

Julsing

Hassouni

et al. 2020

IJMS

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(1) Background: RX-3117 (fluorocyclopentenyl-cytosine) is a cytidine analog that inhibits DNA methyltransferase 1 (DNMT1). We investigated the mechanism and potential of RX-3117 as a demethylating agent in several in vitro models. (2) Methods: we used western blotting to measure expression of several proteins known to be down-regulated by DNA methylation: O6-methylguanine-DNA methyltransferase (MGMT) and the tumor-suppressor genes, p16 and E-cadherin. Transport of methotrexate (MTX) mediated by the proton-coupled folate transporter (PCFT) was used as a functional assay. (3) Results: RX-3117 treatment decreased total DNA-cytosine-methylation in A549 non-small cell lung cancer (NSCLC) cells, and induced protein expression of MGMT, p16 and E-cadherin in A549 and SW1573 NSCLC cells. Leukemic CCRF-CEM cells and the MTX-resistant variant (CEM/MTX, with a deficient reduced folate carrier) have a very low expression of PCFT due to promoter hypermethylation. In CEM/MTX cells, pre-treatment with RX-3117 increased PCFT-mediated MTX uptake 8-fold, and in CEM cells 4-fold. With the reference hypomethylating agent 5-aza-2′-deoxycytidine similar values were obtained. RX-3117 also increased PCFT gene expression and PCFT protein. (4) Conclusion: RX-3117 down-regulates DNMT1, leading to hypomethylation of DNA. From the increased protein expression of tumor-suppressor genes and functional activation of PCFT, we concluded that RX-3117 might have induced hypomethylation of the promotor.

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Re-emerging Antimetabolites with Novel Mechanism of Action with Respect to Epigenetic Regulation: Basic Aspects

Cited by 5 publications

References 106 publications

DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors.

DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors.

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

RX-3117 (Fluorocyclopentenyl-Cytosine)-Mediated Down-Regulation of DNA Methyltransferase 1 Leads to Protein Expression of Tumor-Suppressor Genes and Increased Functionality of the Proton-Coupled Folate Carrier

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