Many pancreatic cancers consume excessive glutamine as a preferable source for anaplerosis, maintenance of proper redox state, and synthesis of intermediates for cancer cell growth and proliferation. Abrogating glutamine metabolism is under investigation to inhibit the proliferation/ growth of glutamine-addicted cancers. In addition, inhibition of the mitochondrial pyruvate carrier (MPC1) can potentially induce cancer cells to become more dependent on glutaminolysis. In this regard, Zaprinast, originally developed as a phosphodiesterase 5 (PDE5) inhibitor, has recently been identified as an inhibitor of both glutaminase as well as MPC1. We compared the growth inhibition effect of Zaprinast against BPTES, a targeted glutaminase inhibitor, and UK5099, a targeted MPC1 inhibitor, as well as the combination of BPTES and UK5099. Using pancreatic ductal adenocarcinoma (PDAC) cells, KRAS mutant (Mia Paca2) and KRAS wildtype (Panc03.27), KRAS mutant neuroendocrine (QGP1), and normal pancreatic epithelial cells (HPNE), Zaprinast alone showed more potent growth inhibition in all tested cells lines than single agent treatment with BPTES or UK5099. Further, Zaprinast effectively depleted mitochondrial reserve respiratory capacity similar to UK5099, rendering mitochondria more vulnerable to oxidative stress or pharmacological inhibitors targeting the electron transport chain. In addition, Zaprinast treatment of cancer cells differentially elevated ROS levels greater than 10-fold compared to normal HPNE cells (ROS levels: Mia Paca2 ~ Panc03.27 > QGP1 > HPNE). However, the increase in ROS levels did not correlate with Zaprinast-induced growth inhibition (IC50: Mia Paca2=300 µM, Panc03.27=110 µM, HPNE=650 µM, QGP1 >1 mM). Although Zaprinast-induced growth inhibition was selective toward adenocarcinoma cells but not the neuroendocrine subtype, the selective Zaprinast-induced elevation of ROS levels toward all cancer subtypes renders possibilities for potential synthetic lethality when combined with other metabolic inhibitors.

Citation Format: Yi Rao, Seth Gammon, David Piwnica-Worms. Differential metabolic targeting of PDAC cells with Zaprinast [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3514.