Abstract A99: DCQ is a hypoxia-activated quinoxaline 1,4-dioxide that reduces breast cancer metastasis

Although tumor hypoxia is associated with the complex processes of tumor metastasis and resistance, and poses significant challenges against traditional cancer treatments, it provides a target for therapy by bioreductive drugs with enhanced cytotoxic activity in the reduced microenvironment of tumors. We identified a potent synthetic quinoxaline di-N-oxide (DCQ) which preferentially targets hypoxic tumors. Here we show that DCQ: 1) Reduces the viability of breast cancer cell lines (MDA-MB-231, MCF-7), 2) Induces reactive oxygen species (ROS)-dependent p53-independent apoptosis, 3) Inhibits the accumulation of hypoxia inducible factor (HIF-1α) via distinct mechanisms in the two cell lines and 4) Significantly reduces hypoxia-induced invasion of breast cancer cell lines in vitro and in vivo. DCQ-induced ROS was associated with increased DNA damage in MDA-MB-231 and MCF-7 cells. The inhibition of HIF-1α accumulation in MCF-7 was in part via the activation of p53 and was accompanied by a decrease in the levels of phosphorylated mTOR, indicating that DCQ-induced reduction of HIF-1α is possibly occurring at the translational level of the protein. HIF-1α reduction was associated with a decrease in p21 and a reversal of the hypoxia-induced VEGF secretion and invasion, which are key processes in tumor metastasis. In MDA-MB-231 cells; however, DCQ reduced HIF-1α through proteasomal degradation, which was accompanied by a reduction of TWIST, a major player in epithelial to mesenchymal transition (EMT). The inhibitory effect of DCQ on hypoxia induced breast cancer invasion was validated in the xenograft model of subdermally injected MDA-MB-231 cells in immune-compromised mice. DCQ significantly increased the survival rate of treated animals. This increase was associated with a reduction of the metastatic dissemination of breast cancer cells into the liver and lungs of DCQ treated mice. Citation Format: Khaled I. Ghattass, Sally El Sitt, Kazem Zibara, Makhlouf MJ Haddadin, Marwan El-Sabban, Hala Ghali-Muhtasib. DCQ is a hypoxia-activated quinoxaline 1,4-dioxide that reduces breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A99.