Abstract B31: Aryl hydrocarbon receptor translocation, CYP1A1 induction and ROS formation: pharmacodynamic markers of sensitivity to antitumor Benzothiazole 5F203 in ovarian cancer

Abstract

Abstract Ovarian malignancies, the second cause of gynaecological cancer death in developed countries possess poor prognoses. Detected at advanced stages of disease (III and IV), the standard of care is cytoreductive surgery followed by platin- and taxane-based chemotherapy. Intrinsic- or acquired resistance to cytotoxic drugs result in significant risk of recurrence; therefore, the discovery of new molecular targets and more effective therapies remain vital. 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. We have previously showed 5F203 activates aryl hydrocarbon receptor (AhR) signaling: enhanced CYP1A1 expression and AhR nuclear translocation in sensitive IGROV-1 ovarian cancer cells. This AhR modulation triggers an antiproliferative/pro-apoptotic activity evoking ROS formation, 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. In this work we further investigated 5F 203 antitumor mechanism of action. We found that 5F203 ROS formation was accompanied by JNK, ERK and P38MAPK phosphorylation only in IGROV-1 sensitive cells. 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. 5F203 induced enhanced CYP1A1 expression, AhR translocation and ROS formation in ascites-isolated ovarian cancer cells that were sensitive to 5F203. We propose that AhR may represent a new molecular target in the treatment of ovarian tumors and 5F203 may exemplify a potential novel treatment. Finally, our studies demonstrate theranostic pharmacodynamic markers of 5F203 activity and provide additional insight into molecular targets of this novel anticancer agent, which may benefit ovarian cancer patients with limited therapeutic options. Note: This abstract was not presented at the conference. Citation Format: Mariana Alejandra Callero, Gabriela Luzzani, Diana De Dios, Bradshaw Tracey, Andrea Loaiza Perez. Aryl hydrocarbon receptor translocation, CYP1A1 induction and ROS formation: pharmacodynamic markers of sensitivity to antitumor Benzothiazole 5F203 in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B31.