| Indanocine, a microtubule-binding indanone and a selective inducer of apoptosis in multidrug-resistant cancer cells. | |
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MedLine Citation:
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PMID: 10655438 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Certain antimitotic drugs have antitumor activities that apparently result from interactions with nontubulin components involved in cell growth and/or apoptotic cell death. Indanocine is a synthetic indanone that has been identified by the National Cancer Institute's Developmental Therapeutics Program as having antiproliferative activity. In this study, we characterized the activity of this new antimitotic drug toward malignant cells. METHODS: We tested antiproliferative activity with an MTT [i.e., 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay, mitochondrial damage and cell cycle perturbations with flow cytometry, caspase-3 activation with fluorometry, alterations of the cytoskeletal components with immunofluorescence, and antimicrotubule activity with a tubulin polymerization assay. RESULTS/CONCLUSIONS: Indanocine is a cytostatic and cytotoxic indanone that blocks tubulin polymerization but, unlike other antimitotic agents, induces apoptotic cell death in stationary-phase multidrug-resistant cancer cells at concentrations that do not impair the viability of normal nonproliferating cells. Of the seven multidrug-resistant cell lines tested, three (i.e., MCF-7/ADR, MES-SA/DX5, and HL-60/ADR) were more sensitive to growth inhibition by indanocine than were their corresponding parental cells. Confluent multidrug-resistant cells (MCF-7/ADR), but not drug-sensitive cancer cells (MCF-7) or normal peripheral blood lymphocytes, underwent apoptotic cell death 8-24 hours after exposure to indanocine, as measured by sequential changes in mitochondrial membrane potential, caspase activity, and DNA fragmentation. Indanocine interacts with tubulin at the colchicine-binding site, potently inhibits tubulin polymerization in vitro, and disrupts the mitotic apparatus in dividing cells. IMPLICATIONS: The sensitivity of stationary multidrug-resistant cancer cells to indanocine suggests that indanocine and related indanones be considered as lead compounds for the development of chemotherapeutic strategies for drug-resistant malignancies. |
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Authors:
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L M Leoni; E Hamel; D Genini; H Shih; C J Carrera; H B Cottam; D A Carson |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of the National Cancer Institute Volume: 92 ISSN: 0027-8874 ISO Abbreviation: J. Natl. Cancer Inst. Publication Date: 2000 Feb |
Date Detail:
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Created Date: 2000-02-28 Completed Date: 2000-02-28 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 7503089 Medline TA: J Natl Cancer Inst Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 217-24 Citation Subset: IM |
Affiliation:
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Department of Medicine and The Sam and Rose Stein Institute for Research on Aging, University of California San Diego, La Jolla 92093, USA. lleoni@ucsd.edu |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Apoptosis / drug effects Caspase 3 Caspases / drug effects Coloring Agents / diagnostic use DNA Fragmentation Drug Resistance, Multiple* Drug Resistance, Neoplasm* Enzyme Activation / drug effects Enzyme Precursors / drug effects Flow Cytometry Fluorescent Antibody Technique Fluorometry Humans Indans / pharmacology* Microtubules / drug effects*, metabolism Neoplasms / drug therapy*, metabolism, pathology Polymers Protein Binding / drug effects Tetrazolium Salts / diagnostic use Thiazoles / diagnostic use Tubulin / drug effects*, metabolism Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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CA78040-01/CA/NCI NIH HHS; GM23200/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Coloring Agents; 0/Enzyme Precursors; 0/Indans; 0/Polymers; 0/Tetrazolium Salts; 0/Thiazoles; 0/Tubulin; 0/indanocine; 298-93-1/thiazolyl blue; EC 3.4.22.-/CASP3 protein, human; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
| Comments/Corrections | |
Comment In:
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J Natl Cancer Inst. 2000 Feb 2;92(3):182-3
[PMID:
10655426
]
J Natl Cancer Inst. 2000 Sep 20;92(18):1535-6 [PMID: 10995814 ] |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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