| Two structurally distinct inhibitors of glycogen synthase kinase 3 induced centromere positive micronuclei in human lymphoblastoid TK6 cells. | |
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MedLine Citation:
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PMID: 18598706 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glycogen synthase kinase 3 (GSK3) is an attractive novel pharmacological target. Inhibition of GSK3 is recently regarded as one of the viable approaches to therapy for Alzheimer's disease, cancer, diabetes mellitus, osteoporosis, and bipolar mood disorder. Here, we have investigated the aneugenic potential of two potent and highly specific inhibitors of GSK3 by using an in vitro micronucleus test with human lymphoblastoid TK6 cells. One inhibitor was a newly synthesized maleimide derivative and the other was a previously known aminopyrimidine derivative. Both compounds elicited statistically significant and concentration-dependent increases in micronucleated cells. One hundred micronuclei (MN) of each were analyzed using centromeric DNA staining with fluorescence in situ hybridization. Both the two structurally distinct compounds induced centromere-positive micronuclei (CMN). Calculated from the frequency of MN cells and the percentage of CMN, CMN cell incidence after treatment with the maleimide compound at 1.2 microM, 2.4 microM, and 4.8 microM was 11.6, 27.7, and 56.3 per 1000 cells, respectively; the negative control was 4.5. CMN cell incidence after the treatment with the aminopyrimidine compound at 1.8 microM, 3.6 microM, and 5.4 microM was 6.7, 9.8 and 17.2 per 1000 cells, respectively. Both compounds exhibited concentration-dependent increase in the number of mitotic cells. The frequency of CMN cells correlated well with mitotic cell incidence after treatment with either compound. Furthermore, both inhibitors induced abnormal mitotic cells with asymmetric mitotic spindles and lagging anaphase chromosomes. These results lend further support to the hypothesis that the inhibition of GSK3 activity affects microtubule function and exhibits an aneugenic mode of action. |
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Authors:
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Masayuki Mishima; Kenji Tanaka; Akira Takeiri; Asako Harada; Chiyomi Kubo; Sachiko Sone; Yoshikazu Nishimura; Yukako Tachibana; Makoto Okazaki |
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Publication Detail:
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Type: Journal Article Date: 2008-06-12 |
Journal Detail:
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Title: Mutation research Volume: 643 ISSN: 0027-5107 ISO Abbreviation: Mutat. Res. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-08-18 Completed Date: 2008-10-23 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0400763 Medline TA: Mutat Res Country: Netherlands |
Other Details:
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Languages: eng Pagination: 29-35 Citation Subset: IM |
Affiliation:
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Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. mishimamsy@chugai-pharm.co.jp |
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| MeSH Terms | |
Descriptor/Qualifier:
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Aneugens
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pharmacology* Blotting, Western Cell Nucleus / genetics Centromere / drug effects*, physiology Enzyme Inhibitors / pharmacology* Flow Cytometry Fluorescent Antibody Technique Glycogen Synthase Kinase 3 / antagonists & inhibitors* Humans In Situ Hybridization, Fluorescence / methods Lymphocytes / cytology, drug effects*, metabolism Maleimides / pharmacology Micronucleus Tests / methods Microtubules / physiology Mitotic Spindle Apparatus / drug effects, genetics Pyrimidines / pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Aneugens; 0/Enzyme Inhibitors; 0/Maleimides; 0/Pyrimidines; 541-59-3/maleimide; 591-54-8/4-aminopyrimidine; EC 2.7.11.26/Glycogen Synthase Kinase 3 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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