title: Effects of novel retinoic acid metabolism blocking agent (VN/14-1) on letrozole-insensitive breast cancer cells.
abstract: 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.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, School of Medicine and the Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201, USA.
authors.forename: Aashvini
authors.initials: A
authors.lastname: Belosay
authors.forename: Angela M H
authors.initials: AM
authors.lastname: Brodie
authors.forename: Vincent C O
authors.initials: VC
authors.lastname: Njar
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D051548:Histone Acetyltransferases / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D000077289:Letrozole; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D056921:Nuclear Receptor Coactivator 3; D010052:Ovariectomy; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D015534:Trans-Activators / Q000378:metabolism; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C496751:4-(1H-imidazol-1-yl)retinoic acid; D051017:Apoptosis Regulatory Proteins; D047072:Aromatase Inhibitors; D018797:Cell Cycle Proteins; D047628:Estrogen Receptor alpha; D006728:Hormones; D007093:Imidazoles; D009570:Nitriles; D015534:Trans-Activators; D014230:Triazoles; D014212:Tretinoin; D000077289:Letrozole; D001141:Aromatase; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3; D020928:Mitogen-Activated Protein Kinases