| Autophagic cell death, polyploidy and senescence induced in breast tumor cells by the substituted pyrrole JG-03-14, a novel microtubule poison. | |
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MedLine Citation:
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PMID: 17692290 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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JG-03-14, a substituted pyrrole that inhibits microtubule polymerization, was screened against MCF-7 (p53 wild type), MDA-MB231 (p53 mutant), MCF-7/caspase 3 and MCF-7/ADR (multidrug resistant) breast tumor cell lines. Cell viability and growth inhibition were assessed by the crystal violet dye assay. Apoptosis was evaluated by the TUNEL assay, cell cycle distribution by flow cytometry, autophagy by acridine orange staining of vesicle formation, and senescence based on beta-galactosidase staining and cell morphology. Our studies indicate that exposure to JG-03-14, at a concentration of 500 nM, induces time-dependent cell death in the MCF-7 and MDA-MB231 cell lines. In MCF-7 cells, a residual surviving cell population was found to be senescent; in contrast, there was no surviving senescent population in treated MDA-MB231 cells. No proliferative recovery was detected over a period of 15 days post-treatment in either cell line. Both the TUNEL assay and FLOW cytometry indicated a relatively limited degree of apoptosis (<10%) in response to drug treatment in MCF-7 cells with more extensive apoptosis (but <20%) in MDA-MB231 cells; acidic vacuole formation indicative of autophagic cell death was relatively extensive in both MCF-7 and MDA-MB231 cells. In addition, JG-03-14 induced the formation of a large hyperdiploid cell population in MDA-MB231 cells. JG-03-14 also demonstrated pronounced anti-proliferative activity in MCF-7/caspase 3 cells and in the MCF-7/ADR cell line. The observation that JG-03-14 promotes autophagic cell death and also retains activity in tumor cells expressing the multidrug resistance pump indicates that novel microtubule poisons of the substituted pyrroles class may hold promise in the treatment of breast cancer. |
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Authors:
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Christopher R Arthur; John T Gupton; Glen E Kellogg; W Andrew Yeudall; Myles C Cabot; Irene F Newsham; David A Gewirtz |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-07-07 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 74 ISSN: 0006-2952 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2007 Oct |
Date Detail:
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Created Date: 2007-08-27 Completed Date: 2007-10-19 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 981-91 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Toxicology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aging
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drug effects Antineoplastic Agents / pharmacology* Autophagy / drug effects* Breast Neoplasms / drug therapy*, metabolism* Caspase 3 / drug effects Cell Line, Tumor Cell Proliferation / drug effects Chromosome Aberrations Drug Resistance, Neoplasm Humans Microtubules / drug effects Molecular Structure Polyploidy* Pyrroles / chemistry, pharmacology* Time Factors |
| Grant Support | |
ID/Acronym/Agency:
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P30 CA16059/CA/NCI NIH HHS; R15 CA067236-03/CA/NCI NIH HHS; R15 CA067236-04/CA/NCI NIH HHS; R15-CA67236/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; 0/Antineoplastic Agents; 0/Pyrroles; EC 3.4.22.-/Caspase 3 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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