title: Biomarkers of sensitivity to potent and selective antitumor 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F203) in ovarian cancer.
abstract: 2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole (5F203, NSC 703786) lysylamide belongs to a novel mechanistic class of antitumor agents. It elicits activity against ovarian, breast, kidney and colorectal cancer models. In sensitive breast cancer cells, 5F203 activates aryl hydrocarbon receptor (AhR) signaling. Herein, we evaluate the role of AhR in 5F203 activity in two ovarian cancer cell lines: IGROV-1 (sensitive to 5F203), SKOV-3 (resistant to this agent). In addition, cancer cells have been isolated from ascites fluid of ovarian cancer patients; sensitivity to 5F203 and concurrent AhR signal transduction has been examined in ascites-isolated ovarian cancer patients' cells. 5F203 induced enhanced CYP1A1 expression, AhR translocation and ROS formation in IGROV-1 cells and ascites-isolated ovarian cancer cells that were sensitive to 5F203. In IGROV-1 cells 5F203-induced ROS formation was accompanied by JNK, ERK and P38MAPK phosphorylation, DNA damage and cell cycle arrest prior to apoptosis. In contrast, 5F203 failed to induce CYP1A1 expression, AhR translocation or oxidative stress in 5F203-resistant SKOV-3 cells, or in ovarian cancer ascites cells inherently resistant to this agent. We propose that AhR may represent a new molecular target in the treatment of ovarian tumors and 5F203 may exemplify a potential novel treatment. Furthermore, putative biomarkers of sensitivity to this agent have been identified.
authors.affiliation: National Scientific Council (CONICET), Ciudad de Buenos Aires, Argentina.
authors.forename: Mariana A
authors.initials: MA
authors.lastname: Callero
authors.forename: Gabriela A
authors.initials: GA
authors.lastname: Luzzani
authors.forename: Diana O
authors.initials: DO
authors.lastname: De Dios
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
authors.forename: Andrea I Loaiza
authors.initials: AI
authors.lastname: Perez
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018613:Microscopy, Confocal; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: C425784:2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D013844:Thiazoles; D019938:Cyclin D1; D019363:Cytochrome P-450 CYP1A1; D053148:Caspase 3
keywords: 5F203; AhR; CYP1A1; OVARIAN CANCER; ROS