Abstract 2565: Aryl hydrocarbon receptor agonist 5F 203 induces oxidative stress triggering DNA damage and cytoglobin up-regulation in human breast cancer cells

Breakthroughs are needed in breast cancer therapy to improve clinical outcomes. Emerging evidence suggests that tumorigenesis stems, in part, from epigenetically silenced tumor suppressor genes (TSGs) and restoring TSGs may represent a viable strategy to treat breast cancer. We previously found that aryl hydrocarbon receptor (AhR) agonist 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) exhibits potent cytotoxicity, increases reactive oxygen species (ROS), induces DNA damage and up-regulates the expression of putative tumor suppressor gene cytoglobin in breast cancer cells. In the current study, we seek to delineate the mechanism by which 5F 203 induces DNA damage and cytoglobin expression in susceptible breast cancer cells. We found that 5F 203 activated p38 mitogen activated protein kinase (p38) and c-Jun-N terminal kinase (JNK) signaling in breast cancer cells. Pretreatment with antioxidant N-acetyl-L-cysteine or AhR inhibitor α-naphthoflavone diminished 5F 203-mediated p38 or JNK activation in a cell context-dependent fashion. Pretreatment with pharmacological inhibitors of p38 or JNK suppressed 5F 203-mediated increases in intracellular ROS to suggest the presence of a positive feedback loop. 5F 203 induced oxidative DNA damage in breast cancer cells but not breast epithelial MCF-10A cells unlike AhR agonist benzo[a]pyrene which induced oxidative DNA damage more indiscriminately. Pretreatment with p38 or JNK inhibitors suppressed 5F 203-induced single strand break formation and cytoglobin mRNA expression in breast cancer cells. Our data show 5F 203 confers anticancer activity in breast cancer cells in part by increasing ROS via a positive feedback loop to sustain p38 and JNK activation resulting in DNA damage and cytoglobin restoration.Citation Format: Leah K. Rowland, Lancelot S. McLean, Petreena Campbell, Cheri N. Watkins, Dain Zylstra, Louisa H. Amis, Maheswari Senthil, Eileen Brantley. Aryl hydrocarbon receptor agonist 5F 203 induces oxidative stress triggering DNA damage and cytoglobin up-regulation in human breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2565. doi:10.1158/1538-7445.AM2015-2565