| Combined low doses of PPARgamma and RXR ligands trigger an intrinsic apoptotic pathway in human breast cancer cells. | |
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MedLine Citation:
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PMID: 19644018 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Ligand activation of peroxisome proliferator-activated receptor (PPAR)gamma and retinoid X receptor (RXR) induces antitumor effects in cancer. We evaluated the ability of combined treatment with nanomolar levels of the PPARgamma ligand rosiglitazone (BRL) and the RXR ligand 9-cis-retinoic acid (9RA) to promote antiproliferative effects in breast cancer cells. BRL and 9RA in combination strongly inhibit of cell viability in MCF-7, MCF-7TR1, SKBR-3, and T-47D breast cancer cells, whereas MCF-10 normal breast epithelial cells are unaffected. In MCF-7 cells, combined treatment with BRL and 9RA up-regulated mRNA and protein levels of both the tumor suppressor p53 and its effector p21(WAF1/Cip1). Functional experiments indicate that the nuclear factor-kappaB site in the p53 promoter is required for the transcriptional response to BRL plus 9RA. We observed that the intrinsic apoptotic pathway in MCF-7 cells displays an ordinated sequence of events, including disruption of mitochondrial membrane potential, release of cytochrome c, strong caspase 9 activation, and, finally, DNA fragmentation. An expression vector for p53 antisense abrogated the biological effect of both ligands, which implicates involvement of p53 in PPARgamma/RXR-dependent activity in all of the human breast malignant cell lines tested. Taken together, our results suggest that multidrug regimens including a combination of PPARgamma and RXR ligands may provide a therapeutic advantage in breast cancer treatment. |
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Authors:
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Daniela Bonofiglio; Erika Cione; Hongyan Qi; Attilio Pingitore; Mariarita Perri; Stefania Catalano; Donatella Vizza; Maria Luisa Panno; Giuseppe Genchi; Suzanne A W Fuqua; Sebastiano Andò |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-07-30 |
Journal Detail:
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Title: The American journal of pathology Volume: 175 ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2009 Sep |
Date Detail:
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Created Date: 2009-09-02 Completed Date: 2009-12-14 Revised Date: 2010-09-02 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 1270-80 Citation Subset: AIM; IM |
Affiliation:
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Faculty of Pharmacy Nutritional and Health Sciences, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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administration & dosage* Apoptosis / drug effects* Breast / cytology, drug effects Breast Neoplasms / drug therapy*, metabolism, pathology* Cell Line, Tumor Dose-Response Relationship, Drug Epithelial Cells / drug effects Female Humans Ligands NF-kappa B / metabolism PPAR gamma / agonists Retinoid X Receptors / agonists Thiazolidinediones / administration & dosage* Tretinoin / administration & dosage* Tumor Suppressor Protein p53 / antagonists & inhibitors, metabolism |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Ligands; 0/NF-kappa B; 0/PPAR gamma; 0/Retinoid X Receptors; 0/Thiazolidinediones; 0/Tumor Suppressor Protein p53; 122320-73-4/rosiglitazone; 302-79-4/Tretinoin; 5300-03-8/alitretinoin |
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