title: AGN193109 is a highly effective antagonist of retinoid action in human ectocervical epithelial cells.
abstract: Retinoids are important physiological agents that regulate epithelial cell differentiation and proliferation. The importance of these agents in regulating growth, development, and differentiation has led to a search for new retinoid agonists and antagonists. In the present manuscript we show that AGN193109, a retinoid analog, is an efficient antagonist of retinoid action in human cervical epithelial cells. Treatment of ECE16-1 cells with natural or synthetic retinoids reduces cytokeratin K5, K6, K14, K16, and K17 levels, increases cytokeratin K7, K8, and K19 levels, increases retinoic acid receptor-beta (RAR beta) mRNA levels, suppresses proliferation, and alters cell morphology. Co-treatment with AGN193109 prevents these responses. Half-maximal and maximal antagonism is observed at a molar ratio of AGN193109: retinoid agonist of 1:1 and 10:1, respectively. When administered alone AGN193109 has no agonist activity. Thus, AGN193109, which binds to RAR alpha, RAR beta, and RAR gamma with Kd values = 2,2, and 3 nm, respectively, but is unable to bind to the retinoid X receptors, is a highly active antagonist of retinoid action in ECE16-1 cells.
authors.affiliation: Department of Physiology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4970 USA.
authors.forename: C
authors.initials: C
authors.lastname: Agarwal
authors.forename: R A
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: A T
authors.initials: AT
authors.lastname: Johnson
authors.forename: E A
authors.initials: EA
authors.lastname: Rorke
authors.forename: R L
authors.initials: RL
authors.lastname: Eckert
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002584:Cervix Uteri / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D009281:Naphthalenes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D009281:Naphthalenes; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C096920:AGN 193109