Abstract 6183: A novel NQO1 bioactivatable drug induces mitochondrial dysfunction and G2/M phase cell cycle arrest to selectively kill pancreatic cancer cells

Abstract

Abstract As a fatal disease with short overall survival, pancreatic cancer is among the top five leading cause of cancer-related deaths worldwide, current therapies against pancreatic cancer lack tumor specificity and generally cause toxic side effects on normal and healthy tissues. Thus, exploring and developing novel tumor-specific agents for treating pancreatic cancer is a critical need. NAD(P)H:quinone oxidoreductase 1 (NQO1) is elevated in the pancreatic cancers whereas it lacks in associated normal tissues. Therefore, NQO1 bioactivatable drugs are promising due to tumor-selective killing NQO1-positive cancer cells. Our previous studies have revealed that the novel NQO1 bioactivatable drug - deoxynyboquinone (DNQ) is ten-fold more potent than the prototypic NQO1 bioactivatable drug β-lapachone to efficiently kill NQO1-positive cancer cells. However, DNQ causes a severe side effect action - high-grade methemoglobinemia that limits its clinical usefulness. Here, we developed a novel DNQ derivative, isopentyl-deoxynboquinone (IP-DNQ), which selectively killed pancreatic ductal adenocarcinoma (PDA) cells in an NQO1-dependent way with an extremely low IC50 (0.1 µM). IP-DNQ evoked massive ROS production and oxidative DNA lesions, resulting in PARP1 hyperactivation and mitochondrial catastrophe. Furthermore, we also observed that IP-DNQ induced G2/M phase cell cycle arrest and promoted programmed necrosis and caspase-dependent apoptosis co-existing in IP-DNQ-treated NQO1-positive pancreatic cancer cells. In addition, IP-DNQ treatment caused extremely low side effect of methemoglobinemia, significantly suppressed tumor growth and extended mice lifespan in orthotopic pancreatic cancer xenograft model. In summary, our findings offer a novel potential therapy against NQO1-positive pancreatic cancers and enable mechanism-based synergy with other anticancer drugs. Citation Format: Xiumei Huang, Lingxiang Jiang, Matthew W. Boudreau, Paul J. Hergenrother. A novel NQO1 bioactivatable drug induces mitochondrial dysfunction and G2/M phase cell cycle arrest to selectively kill pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6183.