Abstract B47: Modulating the NQO1-dependent ‘kiss of death’ mechanism of action of NQO1 bioactivatable drugs

Abstract

Abstract Metabolic adaptations in tumors are necessary to balance the need for cellular energy supply, macromoleclar biosynthesis and maintenance of redox balance. A critical molecule produced as a result of this altered metabolism is nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is a critical co-factor that provides reducing power to maintain cytoprotective concentrations of reduced glutathione against reactive oxygen species (ROS) that are produced during rapid growth and proliferation. In pancreatic cancers, NADPH can be formed by the NAD+ salvage pathway through the enzyme, Nicotinamide phosphoribosyltransferase (NamPT), as well as through the non-canonical metabolism of glutamine through glutaminase-1 (GLS1). While NamPT and GLS1 inhibitors have shown some anti-tumor activity in vitro and in vivo, these inhibitors lack tumor specificity and can have an extensive toxicity profile due to the requirement of NADPH synthesis in proliferating normal cells/tissue. We recently discovered that NAD(P)H:quinone oxidoreductase 1 (NQO1) levels were elevated 5- to 40-fold in >80% of pancreatic tumors vs associated normal tissue. As important, we noted that catalase levels were inversely expressed comparatively, elevated in normal and suppressed in tumor tissue. Thus, NQO1 represents a unique target to exploit for the therapeutic elimination of pancreatic cancers. While NQO1 is normally a detoxifying (Phase II) enzyme, we have discovered two unique classes of compounds that are ‘bioactivated’ in a futile redox cycle by the enzyme. NQO1 bioactivatable drugs, such as β-lapachone (β-lap) and deoxynyboquinone (DNQ), generate hydrogen peroxide as a mechanism to hyperactivate poly(ADP-ribose) polymerase 1 (PARP1), and to rapidly deplete NAD+ and ATP in a selective manner to kill tumors. Normal cells are protected due to low NQO1 and relatively high Catalase levels. We found that the tumor specificity and efficacy of NamPT or GLS1 inhibition can be greatly increased when small molecule NamPT inhibitors (e.g., FK866) or GLS1 inhibitors (e.g., BPTES) are used in combination with NQO1-bioactivatable drugs. With combination treatment, cells are primed for ROS-mediated damage due to reduced glutathione and NADPH levels; they are unable to recover ATP, NAD+, and NADPH synthesis even after only a 2 h exposure to NQO1 bioactivatable drugs, and they rapidly die through a caspase-independent, parthanatos (programmed necrosis) mechanism. Our findings indicate that NQO1-bioactivatable drugs may improve the sensitivities of clinical grade GLS1 and NamPT inhibitors in pancreatic cancer patients. This work was supported by an AACR/Pancreatic Cancer Action Network - George and June Block Foundation - Innovator Award and an NIH/NCI R01 CA102971 grant to DAB. Citation Format: Zachary Moore, Gaurab Chakrabarti, Costas Lyssiotis, Ralph Deberardinis, Boothman A. David. Modulating the NQO1-dependent ‘kiss of death’ mechanism of action of NQO1 bioactivatable drugs. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B47.