生物活性

• 描述RRx-001 exerts its anti-proliferative effect, at least partially, through interference with glucose 6 phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway, responsible for maintaining adequate levels of the major cellular reductant, NADPH. RRx-001 affects glucose and G6PD enzyme activity in three different cancer cell lines namely Hep G2, CACO-2, and HT-29. RRx-001 induced G6PD inhibition and increased glucose consumption in a concentration dependent fashion. RRx-001 induces p53 and PARP-1 via generation of ROS/RNS. It exerts anticancer activity, at least in part, by interfering with 3 crucial metabolic demands of rapidly proliferating cells: bioenergetics, macromolecular biosynthesis, and manipulation of cellular cytosolic redox homeostasis. RRx-001 mediates nuclear translocation of Nrf2 and the activation of expression of its downstream enzymes HO-1 and NQO1 in tumor cells. Apart from epigenetic alterations, RRx-001 acts via pleiotropic mechanisms including redox signaling and redox-induced dysregulation of many different signal pathways such as Nrf2, p53, PARP cleavage, HIF1 alpha, and G6PD activity. It also triggers p53 and p21 activity in response to double-stranded DNA breaks as well as deregulates cancer cellular energetics and metabolism. RRx-001 is a potent activator of the Nrf2-ARE signaling pathway via ROS/RNS generation.