Alpha anomer of 5-aza-2'-deoxycytidine down-regulates hTERT mRNA expression in human leukemia HL-60 cells
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
18045574
DOI
10.1016/j.bcp.2007.10.018
PII: S0006-2952(07)00697-1
Knihovny.cz E-resources
- MeSH
- Azacitidine analogs & derivatives chemistry pharmacology MeSH
- Decitabine MeSH
- DNA metabolism MeSH
- Down-Regulation MeSH
- HL-60 Cells MeSH
- Humans MeSH
- RNA, Messenger biosynthesis MeSH
- DNA Methylation drug effects MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Antimetabolites, Antineoplastic pharmacology MeSH
- S-Adenosylhomocysteine metabolism MeSH
- S-Adenosylmethionine metabolism MeSH
- Stereoisomerism MeSH
- Telomerase biosynthesis MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Azacitidine MeSH
- Decitabine MeSH
- DNA MeSH
- RNA, Messenger MeSH
- Antimetabolites, Antineoplastic MeSH
- S-Adenosylhomocysteine MeSH
- S-Adenosylmethionine MeSH
- Telomerase MeSH
- TERT protein, human MeSH Browser
DNA methylation inhibitors are being extensively studied as potential anticancer agents. In the present study, we compared the capability of alpha anomer of 5-aza-2'-deoxycytidine (alpha-5-azadCyd) to induce down-regulation of hTERT expression in HL-60 cells with other nucleoside analogs that act as DNA methylation inhibitors: beta-5-azadCyd (decitabine), (S)-9-(2,3-dihydroxypropyl)adenine [(S)-DHPA], isobutyl ester of (R,S)-3-(adenin-9-yl)-2-hydroxypropanoic acid [(R,S)-AHPA-ibu] and prospective DNA methylation inhibitors (S)-1-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine [(S)-HPMPazaC] and 5-fluoro-zebularine (F-PymRf). Exposure to alpha-5-azadCyd induced the down-regulation of hTERT expression in low micromolar concentrations (0.05-50 microM). A more cytotoxic beta anomer caused a transient up-regulation of hTERT and a subsequent reduction in hTERT mRNA levels at concentrations more than 10 times below its GIC50 value. In this respect, (S)-DHPA and (R,S)-AHPA-ibu were less efficient, since a similar effect was achieved at concentrations above their GIC(50). In contrast, F-PymRf treatment resulted in up to a three-fold induction of hTERT expression within a broad range of concentrations. In all cases, the down-regulation of hTERT expression was concentration-dependent. The correlation was found between c-myc overexpression and transiently elevated hTERT expression after treatment with all tested compounds except for alpha-5-azadCyd and (S)-HPMPazaC. Although the primary task of hypomethylating agents in anticancer therapy lies in reactivation of silenced tumour-suppressor genes, the inhibition of hTERT expression might also be a fruitful clinical effect of this approach.
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