Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation

Rius, Maria; Stresemann, Carlo; Keller, Daniela; Brom, Manuela; Schirrmacher, Esther; Keppler, Dietrich; Lyko, Frank

doi:10.1158/1535-7163.mct-08-0743

Cited by 57 publications

(56 citation statements)

References 34 publications

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“…Consequently, the difference between the two epigenetic drugs results in differential cellular responses and causes distinct changes in the gene expression patterns of cells treated with Aza-dC and Aza [44,45] . Intracellular uptake of Aza-dC is mediated by the human concentrative nucleoside transporter 1 HCNT1, also known as SLC28A1 [46] . Once inside cells, Aza-dC is then phosphorylated by deoxycytidine kinase yielding AzadCMP.…”

Section: Inhibition Of Dnmts By Aza-dcmentioning

confidence: 99%

Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries

Wongtrakoongate

2015

WJSC

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Recent advances in stem cell biology have shed light on how normal stem and progenitor cells can evolve to acquire malignant characteristics during tumorigenesis. The cancer counterparts of normal stem and progenitor cells might be occurred through alterations of stem cell fates including an increase in self-renewal capability and a decrease in differentiation and/or apoptosis. This oncogenic evolution of cancer stem and progenitor cells, which often associates with aggressive phenotypes of the tumorigenic cells, is controlled in part by dysregulated epigenetic mechanisms including aberrant DNA methylation leading to abnormal epigenetic memory. Epigenetic therapy by targeting DNA methyltransferases (DNMT) 1, DNMT3Aand DNMT3B via 5-Azacytidine (Aza) and 5-Aza-2'-deoxycytidine (Aza-dC) has proved to be successful toward treatment of hematologic neoplasms especially for patients with myelodysplastic syndrome. In this review, I summarize the current knowledge of mechanisms underlying the inhibition of DNA methylation by Aza and Aza-dC, and of their apoptotic-and differentiation-inducing effects on cancer stem and progenitor cells in leukemia, medulloblastoma, glioblastoma, neuroblastoma, prostate cancer, pancreatic cancer and testicular germ cell tumors. Since cancer stem and progenitor cells are implicated in cancer aggressiveness such as tumor formation, progression, metastasis and recurrence, I propose that effective therapeutic strategies might be achieved through eradication of cancer stem and progenitor cells by targeting the DNA methylation machineries to interfere their "malignant memory". Core tip: Several types of cancers can be developed from genetic and/or epigenetic instabilities of stem and progenitor cells. Epigenetic abnormality involving dysregulation of DNA methylation has been reported to implicate in cancer aggressiveness. Inhibition of DNA methyltransferase activity by DNA methylation inhibitors has shown promising results toward treatment of myelodysplastic syndrome, a disease associated with leukemic stem cells. This review summarizes evidences which are pertinent to the antitumorigenic potential of DNA methylation inhibitors 5-Azacytidine and 5-Aza-2'-deoxycytidine on cancer stem and progenitor cells including those of leukemia and other solid tumors.Wongtrakoongate P. Epigenetic therapy of cancer stem and REVIEWSubmit a

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Section: Inhibition Of Dnmts By Aza-dcmentioning

confidence: 99%

Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries

Wongtrakoongate

2015

WJSC

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“…As hENT transporters show ubiquitous expression, they can have a major role in the sensitivity and resistance of cancer cells to azanucleoside DNMT inhibitors. The ability of hCNT transporters to mediate cellular uptake of 5-azacytidine and decitabine (Rius et al, 2009) probably becomes more relevant for the treatment of epithelial cell-derived tumors, where the expression levels of hCNT proteins can be higher.…”

Section: Metabolic Activation and Cellular Transport Of Dnmt Inhibitorsmentioning

confidence: 99%

Epigenetic cancer therapy: rationales, targets and drugs

2011

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The fundamental role of altered epigenetic modification patterns in tumorigenesis establishes epigenetic regulatory enzymes as important targets for cancer therapy. Over the past few years, several drugs with an epigenetic activity have received approval for the treatment of cancer patients, which has led to a detailed characterization of their modes of action. The results showed that both established drug classes, the histone deacetylase (HDAC) inhibitors and the DNA methyltransferase inhibitors, show substantial limitations in their epigenetic specificity. HDAC inhibitors are highly specific drugs, but the enzymes have a broad substrate specificity and deacetylate numerous proteins that are not associated with epigenetic regulation. Similarly, the induction of global DNA demethylation by non-specific inhibition of DNA methyltransferases shows pleiotropic effects on epigenetic regulation with no apparent tumor-specificity. Second-generation azanucleoside drugs have integrated the knowledge about the cellular uptake and metabolization pathways, but do not show any increased specificity for cancer epigenotypes. As such, the traditional rationale of epigenetic cancer therapy appears to be in need of refinement, as we move from the global inhibition of epigenetic modifications toward the identification and targeting of tumor-specific epigenetic programs. Recent studies have identified epigenetic mechanisms that promote self-renewal and developmental plasticity in cancer cells. Druggable somatic mutations in the corresponding epigenetic regulators are beginning to be identified and should facilitate the development of epigenetic therapy approaches with improved tumor specificity.

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“…12,13 A second reason is the need of particular variably expressed nucleoside transporters for cellular uptake. 14 There are two main strategies to overcome these obstacles. The first is to change the drug structure by chemical reactions like esterification.…”

Section: -Azacytidine Was First Synthesized In 1963mentioning

confidence: 99%

Enhanced in Vitro Anti-Tumor Activity of 5-Azacytidine by Entrapment into Solid Lipid Nanoparticles

Jahanfar¹,

Hasani²,

Shanebandi³

et al. 2016

Adv Pharm Bull

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Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation

Cited by 57 publications

References 34 publications

Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries

Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries

Epigenetic cancer therapy: rationales, targets and drugs

Enhanced in Vitro Anti-Tumor Activity of 5-Azacytidine by Entrapment into Solid Lipid Nanoparticles

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