Abstract 531: Treatment of pancreatic adenocarcinoma with omeprazole

Abstract Background: Pancreatic adenocarcinoma (PADC) is associated with poor clinical outcomes that show resistance to apoptosis. Therefore, we explored an off-label use of Omeprazole to discover its effect on PADC. Our goal was to expose underlying cellular processes, namely autophagy, which are differentially regulated by Omeprazole to aid in treatment design and improve patient outcomes. Methods: Freshly cultured S2VP10 and Panc1 cells were given 50uM and 500uM Omeprazole treatment for 4-hours. Neutral Red (NR), Acridine Orange (AO), and LysoTracker stains were used to assess viability and lysosomal activity. Immunocytochemistry (ICC) in S2VP10 and Suit2 Cells was used to examine the activity of proton-sensing ion channels ASIC1 and ASIC3 following 50uM Omeprazole treatment. For AO, LysoTracker, and ICC experiments, analysis of fluorescence was performed using Nikon NIS Elements to trace relevant regions and normalize to region area. Significance was determined using Kruskal-Wallis tests followed by pairwise Wilcoxon pos hoc tests. Differences were considered statistically significant at p<0.05. Results: Following Omeprazole treatment, mean NR fluorescence decreased by 54.5% and 6.0% respectively for 500uM treatment of S2VP10 and Panc1 cells. AO staining of S2VP10 cells after 4-hour 500uM treatment showed a 58.2% increase in red fluorescence indicative of autophagosomes and lysosomes. This finding is supported by qualitative analysis of LysoTracker staining. Significantly increased ASIC1 and ASIC3 staining was observed for the 4-hour treatment groups compared to controls in S2VP10 and Suit2 cells lines. Discussion: Our results show that Omeprazole, a proton pump inhibitor, has a significant effect on the proton compartmentalization within pancreatic cancer. Treatment of PDAC remains challenging due to its enhanced autophagy expression and low extracellular pH which enables cell survival despite nutrient deprivation. We have shown that use of proton inhibitors like Omeprazole disrupt autophagy and cytoprotective mechanisms. Exploiting this, may help to reduce chemoresistance in PDAC. Citation Format: Karl N. Thomas, Rohit Singh, William E. Grizzle, Lacey R. McNally. Treatment of pancreatic adenocarcinoma with omeprazole [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 531.