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Biomarkers of sensitivity to potent and selective antitumor 2‐(4‐amino‐3‐methylphenyl)‐5‐fluorobenzothiazole (5F203) in ovarian cancer
Author(s) -
Callero Mariana A.,
Luzzani Gabriela A.,
De Dios Diana O.,
Bradshaw Tracey D.,
Loaiza Perez Andrea I.
Publication year - 2013
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.24589
Subject(s) - ovarian cancer , cancer research , ascites , aryl hydrocarbon receptor , apoptosis , cancer , signal transduction , cancer cell , biology , chemistry , endocrinology , medicine , microbiology and biotechnology , biochemistry , gene , transcription factor
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. J. Cell. Biochem. 114: 2392–2404, 2013. © 2013 Wiley Periodicals, Inc.