Journal of Cellular Biochemistry

Biomarkers of sensitivity to potent and selective antitumor 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F203) in ovarian cancer

Authors

  • Mariana A. Callero,

    1. National Scientific Council (CONICET), Ciudad de Buenos Aires, Argentina
    2. Research Area, Institute of Oncology Ángel H. Roffo, University of Buenos Aires, Ciudad de Buenos Aires, Argentina
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  • Gabriela A. Luzzani,

    1. National Scientific Council (CONICET), Ciudad de Buenos Aires, Argentina
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  • Diana O. De Dios,

    1. Gynecologic Oncology Department, Institute of Oncology Ángel H. Roffo, University of Buenos Aires, Ciudad de Buenos Aires, Argentina
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  • Tracey D. Bradshaw,

    1. Centre for Biomolecular Science, University of Nottingham, Nottingham, UK
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  • Andrea I. Loaiza Perez

    Corresponding author
    1. Research Area, Institute of Oncology Ángel H. Roffo, University of Buenos Aires, Ciudad de Buenos Aires, Argentina
    • National Scientific Council (CONICET), Ciudad de Buenos Aires, Argentina
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Correspondence to: Dr. Andrea I. Loaiza Perez, Research Area, Institute of Oncology Ángel H. Roffo, University of Buenos Aires, Avenue San Martín 5481, C1417DTB, Ciudad de Buenos Aires, Argentina.

E-mail: l oaizaa2012@gmail.com

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. J. Cell. Biochem. 114: 2392–2404, 2013. © 2013 Wiley Periodicals, Inc.

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