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

Abstract

Abstract 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.