title: The antitumor drug candidate 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole induces NF-kappaB activity in drug-sensitive MCF-7 cells.
abstract: 2-(4-Amino-3-methylphenyl)-5-fluoro-benzothiazole (5F 203) potently inhibits MCF-7 breast cancer cell growth in part by activating the aryl hydrocarbon receptor (AhR) signaling pathway. Ligands for the AhR (i.e. dioxin) have also been shown to modulate the NF-kappaB signaling cascade, affecting physiological processes such as cellular immunity, inflammation, proliferation and survival. The objective of this study was to investigate the effect of 5F 203 treatment on the NF-kappaB signaling pathway in breast cancer cells. Exposure of MCF-7 cells to 5F 203 increased protein-DNA complex formation on the NF-kappaB-responsive element as determined by electrophoretic mobility shift assay, but this effect was eliminated in MDA-MB-435 cells, which are resistant to the antiproliferative effects of 5F 203. An increase in NF-kappaB-dependent transcriptional activity was confirmed by a significant increase in NF-kappaB-dependent reporter activity in sensitive MCF-7 cells, which was absent in resistant MDA-MB-435 cells and AhR-deficient subclones of MCF-7 cells. Inhibition of NF-kappaB activation enhanced the increase in xenobiotic response element-dependent reporter activity in MCF-7 cells when treated with 5F 203. The drug candidate 5F 203 also induced mRNA levels of IL-6, an NF-kappaB-responsive gene, in MCF-7 cells, but not in MDA-MB-435 cells, as determined by quantitative RT-PCR. These findings suggest that 5F 203 activation of the NF-kappaB signaling cascade may contribute to 5F 203-mediated anticancer activity in human breast cancer MCF-7 cells.
authors.affiliation: Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute-Frederick, NIH, Frederick, MD, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Brantley
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.forename: Sherman F
authors.initials: SF
authors.lastname: Stinson
authors.forename: Valentina
authors.initials: V
authors.lastname: Trapani
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Hose
authors.forename: Henry P
authors.initials: HP
authors.lastname: Ciolino
authors.forename: Grace C
authors.initials: GC
authors.lastname: Yeh
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: Edward A
authors.initials: EA
authors.lastname: Sausville
authors.forename: Andrea I
authors.initials: AI
authors.lastname: Loaiza-Pérez
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000819:agonists* / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D014158:Transcription, Genetic
chemical_list: C425784:2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole; D000970:Antineoplastic Agents; D015850:Interleukin-6; D016328:NF-kappa B; D018336:Receptors, Aryl Hydrocarbon; D013844:Thiazoles; D008156:Luciferases