title: Benzimidazoles diminish ERE transcriptional activity and cell growth in breast cancer cells.
abstract: Estrogen receptors (ERα and ERβ) are members of the nuclear receptor superfamily. They regulate the transcription of estrogen-responsive genes and mediate numerous estrogen related diseases (i.e., fertility, osteoporosis, cancer, etc.). As such, ERs are potentially useful targets for developing therapies and diagnostic tools for hormonally responsive human breast cancers. In this work, two benzimidazole-based sulfonamides originally designed to reduce proliferation in prostate cancer, have been evaluated for their ability to modulate growth in estrogen dependent and independent cell lines (MCF-7 and MDA-MB 231) using cell viability assays. The molecules reduced growth in MCF-7 cells, but differed in their impact on the growth of MDA-MB 231 cells. Although both molecules reduced estrogen response element (ERE) transcriptional activity in a dose dependent manner, the contrasting activity in the MDA-MB-231 cells seems to suggest that the molecules may act through alternate ER-mediated pathways. Further, the methyl analog showed modest selectivity for the ERβ receptor in an ER gene expression array panel, while the naphthyl analog did not significantly alter gene expression. The molecules were docked in the ligand binding domains of the ERα-antagonist and ERβ-agonist crystal structures to evaluate the potential of the molecules to interact with the receptors. The computational analysis complimented the results obtained in the assay of transcriptional activity and gene expression suggesting that the molecules upregulate ERβ activity while down regulating that of ERα.
authors.affiliation: Department of Chemistry, College of Arts and Sciences, Xavier University of Louisiana, New Orleans, LA, USA.
authors.forename: Florastina
authors.initials: F
authors.lastname: Payton-Stewart
authors.affiliation: Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA, USA.
authors.forename: Syreeta L
authors.initials: SL
authors.lastname: Tilghman
authors.affiliation: Division of Clinical and Administrative Sciences, College of Pharmacy Xavier University of Louisiana, New Orleans, LA, USA.
authors.forename: LaKeisha G
authors.initials: LG
authors.lastname: Williams
authors.affiliation: Department of Chemistry, Spelman College, Atlanta, GA, USA. Electronic address: lwinfield@spelman.edu.
authors.forename: Leyte L
authors.initials: LL
authors.lastname: Winfield
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008958:Models, Molecular; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D001562:Benzimidazoles; D011960:Receptors, Estrogen
keywords: Benzimidazole; Breast cancer; Celecoxib; Docking; Estrogen receptors