Indanocine, a microtubule-binding indanone and a selective inducer of apoptosis in multidrug-resistant cancer cells.
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 Therap...
| Published in: | JNCI: Journal of the National Cancer Institute Vol. 92; no. 3; pp. 217 - 225 |
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| Main Authors: | , , , , , , , , , , , , , |
| Format: | research Journal Article |
| Published: |
Oxford University Press / USA
02/02/2000
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=2771986&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 2771986 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00278874 JNC jtl: JNCI: Journal of the National Cancer Institute issn: 00278874 maglogo: N pubinfo: dt: 02/02/2000 vid: 92 iid: 3 pid: 622 pub: Oxford University Press / USA artinfo: ui: 2771986 2771986 NLM10655438 2771986 10.1093/jnci/92.3.217 NLM10655438 2771986 ppf: 217 ppct: 8 formats: tig: atl: Indanocine, a microtubule-binding indanone and a selective inducer of apoptosis in multidrug-resistant cancer cells. aug: au: Leoni, Lorenzo M. Hamel, Ernest Genini, Davide Shih, Hsiencheng Carrera, Carlos J. Cottam, Howard B. Carson, Dennis A. Leoni, L M Hamel, E Genini, D Shih, H Carrera, C J Cottam, H B Carson, D A affil: Department of Medicine and The Sam and Rose Stein Institute for Research on Aging, University of California San Diego, La Jolla 92093, USA sug: subj: Hydrocarbons Pharmacodynamics Nerve Tissue Proteins Drug Effects Drug Resistance Neoplasms Drug Therapy Cytoplasm Drug Effects Drug Resistance, Neoplasm Antineoplastic Agents Pharmacodynamics Tumor Cells, Cultured DNA Neoplasms Pathology Biochemical Phenomena Drug Effects Human Nerve Tissue Proteins Metabolism Dyes Thiazoles Peptide Hydrolases Drug Effects Flow Cytometry Enzymes Drug Effects Fluorometry Apoptosis Drug Effects Fluorescent Antibody Technique Heterocyclic Compounds Cytoplasm Metabolism Proteins Neoplasms Metabolism Polymers Validation Studies Comparative Studies Evaluation Research Multicenter Studies ab: 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. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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