| Effects of novel retinoic acid metabolism blocking agent (VN/14-1) on letrozole-insensitive breast cancer cells. | |
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MedLine Citation:
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PMID: 17145897 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Aromatase inhibitors are proving to be more effective than tamoxifen for postmenopausal estrogen receptor (ER)-positive breast cancer. However, the inevitable development of resistance to treatment is a concern. We investigated the effects of novel retinoic acid metabolism blocking agent, VN/14-1, in overcoming letrozole resistance in long-term letrozole cultured (LTLC) cells. Compared with MCF-7 cells stably transfected with aromatase (MCF-7Ca), LTLC cells were no longer sensitive to growth inhibition by aromatase inhibitors. The HER-2/phosphorylated mitogen-activated protein kinase (pMAPK) growth factor signaling pathways were activated, and ERalpha and coactivator amplified in breast cancer 1 (AIB1) were up-regulated approximately 3-fold in LTLC cells. VN/14-1 inhibited aromatase activity and growth values of in MCF-7Ca cells with IC(50) of 8.5 and 10.5 nmol/L, respectively. In human placental microsomes, aromatase activity was inhibited with IC(50) of 8.0 pmol/L. The IC(50) in LTLC cells was 0.83 nmol/L, similar to letrozole (IC(50), 0.3 nmol/L) in MCF-7Ca cells. LTLC cells were 10-fold more sensitive to growth inhibition by VN/14-1 than MCF-7Ca cells. VN/14-1 treatment effectively down-regulated ERalpha, AIB1, pMAPK, HER-2, cyclin D1, cyclin-dependent kinase 4 (CDK4), and Bcl2 and up-regulated cytokeratins 8/18, Bad, and Bax. Tumor growth of LTLC cells in ovariectomized nude mice was independent of estrogens but was inhibited by VN/14-1 (20 mg/kg/d; P < 0.002). Decreases in ERalpha, cyclin D1, CDK4, and pMAPK and up-regulation of cytokeratins, Bad, and Bax with VN/14-1 in tumor samples may be responsible for the efficacy of this compound in inhibiting LTLC cell growth in vitro and in vivo. |
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Authors:
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Aashvini Belosay; Angela M H Brodie; Vincent C O Njar |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
Journal Detail:
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Title: Cancer research Volume: 66 ISSN: 0008-5472 ISO Abbreviation: Cancer Res. Publication Date: 2006 Dec |
Date Detail:
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Created Date: 2006-12-05 Completed Date: 2007-01-10 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 11485-93 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Experimental Therapeutics, School of Medicine and the Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis Regulatory Proteins / metabolism Aromatase / metabolism Aromatase Inhibitors / pharmacology Blotting, Western Breast Neoplasms / drug therapy, metabolism*, pathology Cell Cycle Proteins / metabolism Cell Line, Tumor Cell Proliferation / drug effects Dose-Response Relationship, Drug Drug Resistance, Neoplasm / drug effects Estrogen Receptor alpha / metabolism Female Histone Acetyltransferases / metabolism Hormones / pharmacology Humans Imidazoles / pharmacology* Mice Mice, Nude Microsomes / drug effects, enzymology Mitogen-Activated Protein Kinases / metabolism Nitriles / pharmacology* Nuclear Receptor Coactivator 3 Ovariectomy Placenta / enzymology Pregnancy Trans-Activators / metabolism Tretinoin / analogs & derivatives*, antagonists & inhibitors, metabolism*, pharmacology Triazoles / pharmacology* Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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CA-62483/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/4-(1H-imidazol-1-yl)retinoic acid; 0/Apoptosis Regulatory Proteins; 0/Aromatase Inhibitors; 0/Cell Cycle Proteins; 0/Estrogen Receptor alpha; 0/Hormones; 0/Imidazoles; 0/Nitriles; 0/Trans-Activators; 0/Triazoles; 112809-51-5/letrozole; 302-79-4/Tretinoin; EC 1.14.14.1/Aromatase; EC 2.3.1.48/Histone Acetyltransferases; EC 2.3.1.48/NCOA3 protein, human; EC 2.3.1.48/Ncoa3 protein, mouse; EC 2.3.1.48/Nuclear Receptor Coactivator 3; EC 2.7.11.24/Mitogen-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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