| Distinct modulation of telomere length in two T-lymphoblastic leukemia cell lines by cytotoxic nucleoside phosphonates PMEG and PMEDAP. | |
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MedLine Citation:
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PMID: 20599933 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have previously shown that PMEG diphosphate (PMEGpp) and PMEDAP diphosphate (PMEDAPpp) inhibit the enzymatic activity of human telomerase in a cell-free assay. Here, we investigated the ability of PMEG and PMEDAP to induce telomere shortening and telomerase inhibition at both transcriptional and activity level in T-lymphoblastic leukemia cells CCRF-CEM and MOLT-4. At defined time points (3days and 9weeks), the telomerase activity and relative levels of hTERT and c-myc mRNA were determined using real-time RT-PCR. Telomere length was measured by the flow-FISH method. Both PMEDAP and PMEG induced telomere shortening in CCRF-CEM cells after 9weeks of exposure by 50% and 20%, respectively, without major impairment of telomerase activity. The effect of the tested compounds on telomere length in MOLT-4 cells was the opposite, with telomere elongation by 50% and 40% after 9-week treatment with PMEDAP and PMEG, respectively. At this time point, telomerase activity in MOLT-4 cells appeared to be slightly higher than that of CCRF-CEM cells, nevertheless no correlation between telomerase activity and telomere length was found. Both compounds down-regulated the expression of hTERT and c-myc mRNA in CCRF-CEM and MOLT-4 cells at 72h in a concentration-dependent manner while prolonged exposure to PMEG or PMEDAP for 9weeks had weaker effects. In conclusion, PMEDAP and PMEG are able to modulate telomere length in leukemic cells and this effect is cell-type specific. It is neither due to direct telomerase inhibition nor impairment of hTERT expression and it is likely to be telomerase-independent. |
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Authors:
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Miroslav Hájek; Viktor Cvilink; Ivan Votruba; Antonín Holý; Helena Mertlíková-Kaiserová |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-22 |
Journal Detail:
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Title: European journal of pharmacology Volume: 643 ISSN: 1879-0712 ISO Abbreviation: Eur. J. Pharmacol. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-07-26 Completed Date: 2010-12-07 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 1254354 Medline TA: Eur J Pharmacol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 6-12 Citation Subset: IM |
Copyright Information:
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Copyright (c) 2010 Elsevier B.V. All rights reserved. |
Affiliation:
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Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenine
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analogs & derivatives*,
pharmacology Antineoplastic Agents / pharmacology* Cell Culture Techniques Cell Line, Tumor Dose-Response Relationship, Drug Electrophoresis, Polyacrylamide Gel Guanine / analogs & derivatives*, pharmacology Humans In Situ Hybridization, Fluorescence Organophosphorus Compounds / pharmacology* Proto-Oncogene Proteins c-myc / biosynthesis* RNA / metabolism Reverse Transcriptase Polymerase Chain Reaction Telomerase / antagonists & inhibitors, biosynthesis* Telomere / drug effects* Time Factors |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/MYC protein, human; 0/Organophosphorus Compounds; 0/Proto-Oncogene Proteins c-myc; 113852-41-8/9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; 114088-58-3/9-((2-phosphonylmethoxy)ethyl)guanine; 63231-63-0/RNA; 73-24-5/Adenine; 73-40-5/Guanine; EC 2.7.7.49/TERT protein, human; EC 2.7.7.49/Telomerase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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