| 9-(2-Phosphonylmethoxyethyl)adenine induces tumor cell differentiation or cell death by blocking cell cycle progression through the S phase. | |
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MedLine Citation:
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PMID: 10392905 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In addition to its inhibitory activity against viral DNA polymerases and reverse transcriptase, the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) also markedly inhibits the replicative cellular DNA polymerases alpha, delta, and epsilon. We have previously shown that PMEA is a strong inducer of differentiation in several in vitro tumor cell models and has marked antitumor potential in vivo. To elucidate the molecular mechanism of the differentiation-inducing activity of PMEA, we have now investigated the effects of the drug on cell proliferation and differentiation, cell cycle regulation, and oncogene expression in the human erythroleukemia K562 cell line. Terminal, irreversible erythroid differentiation of PMEA-treated K562 cells was evidenced by hemoglobin production, increased expression of glycophorin A on the K562 cell membrane, and induction of acetylcholinesterase activity. After exposure to PMEA, K562 cell cultures displayed a marked retardation of S-phase progression, leading to a severe perturbation of the normal cell cycle distribution pattern. Whereas no substantial changes in c-myc mRNA levels and p21, PCNA, cdc2, and CDK2 protein levels were noted in PMEA-treated K562 cells, there was a marked accumulation of cyclin A and, most strikingly, cyclins E and B1. A similar picture of cell cycle deregulation was also observed in PMEA-exposed human myeloid THP-1 cells. However, in contrast to the strong differentiation-inducing activity of PMEA in K562 cells, the drug completely failed to induce monocytic maturation of human myeloid THP-1 cells. On the contrary, THP-1 cells underwent apoptotic cell death in the presence of PMEA, as demonstrated by prelytic, intracellular DNA fragmentation and the binding of annexin V to the cell surface. We hypothesize that, depending on the nature of the tumor cell line, PMEA triggers a process of either differentiation or apoptosis by the uncoupling of normally integrated cell cycle processes through inhibition of DNA replication during the S phase. |
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Authors:
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S Hatse; D Schols; E De Clercq; J Balzarini |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research Volume: 10 ISSN: 1044-9523 ISO Abbreviation: Cell Growth Differ. Publication Date: 1999 Jun |
Date Detail:
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Created Date: 1999-09-08 Completed Date: 1999-09-08 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9100024 Medline TA: Cell Growth Differ Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 435-46 Citation Subset: IM |
Affiliation:
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Rega Institute for Medical Research, Katholicke Universitat Leuven, Belgium. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenine
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analogs & derivatives*,
chemistry,
metabolism,
pharmacology Annexin A5 / metabolism Apoptosis / drug effects* Cell Cycle / drug effects Cell Differentiation / drug effects Cell Division / drug effects Cell Survival / drug effects Cyclin A / biosynthesis Cyclin B / biosynthesis Cyclin B1 Cyclin E / biosynthesis DNA Fragmentation Flow Cytometry / methods Gene Expression / drug effects Growth Inhibitors / chemistry, metabolism*, pharmacology Humans K562 Cells Molecular Structure Monocytes / drug effects Phosphonic Acids* Proto-Oncogene Proteins c-myc / genetics RNA, Messenger S Phase |
| Chemical | |
Reg. No./Substance:
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0/Annexin A5; 0/CCNB1 protein, human; 0/Cyclin A; 0/Cyclin B; 0/Cyclin B1; 0/Cyclin E; 0/Growth Inhibitors; 0/Phosphonic Acids; 0/Proto-Oncogene Proteins c-myc; 0/RNA, Messenger; 106941-25-7/adefovir; 73-24-5/Adenine |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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