Document Detail

Combined low doses of PPARgamma and RXR ligands trigger an intrinsic apoptotic pathway in human breast cancer cells.
MedLine Citation:
PMID:  19644018     Owner:  NLM     Status:  MEDLINE    
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.
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:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-07-30
Journal Detail:
Title:  The American journal of pathology     Volume:  175     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-02     Completed Date:  2009-12-14     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1270-80     Citation Subset:  AIM; IM    
Faculty of Pharmacy Nutritional and Health Sciences, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy.
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MeSH Terms
Antineoplastic Agents / 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
NF-kappa B / metabolism
PPAR gamma / agonists
Retinoid X Receptors / agonists
Thiazolidinediones / administration & dosage*
Tretinoin / administration & dosage*
Tumor Suppressor Protein p53 / antagonists & inhibitors,  metabolism
Reg. No./Substance:
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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