LAUSR

Simple Summary Drug repurposing in combination with clinical standard chemotherapeutics opens a novel and promising clinical treatment approach for patients with pancreatic cancer. This report presents a novel therapeutic effect of the combination of aspirin and oseltamivir phosphate with chemotherapeutic gemcitabine as a treatment option for pancreatic cancer. The data suggest that targeting mammalian neuraminidase-1 on pancreatic cancer cells with these repurposed drugs is crucial for modulating cell proliferation, invasion, clonogenicity, and migration. These promising results warrant additional investigation to assess the potential of translating into the clinical setting to improve the cancer patient prognosis for an otherwise fatal disease. Abstract Resistance to chemotherapeutics and high metastatic rates contribute to the abysmal survival rate in patients with pancreatic cancer. An alternate approach for treating human pancreatic cancer involves repurposing the anti-inflammatory drug, aspirin (ASA), with oseltamivir phosphate (OP) in combination with the standard chemotherapeutic agent, gemcitabine (GEM). The question is whether treatment with ASA and OP can sensitize cancer cells to the cytotoxicity induced by GEM and limit the development of chemoresistance. To assess the key survival pathways critical for pancreatic cancer progression, we used the AlamarBlue cytotoxicity assay to determine the cell viability and combination index for the drug combinations, flow cytometric analysis of annexin V apoptosis assay to detect apoptotic and necrotic cells, fluorometric QCM™ chemotaxis migration assay to assess cellular migration, fluorometric extracellular matrix (ECM) cell adhesion array kit to assess the expression of the ECM proteins, scratch wound assay using the 96-well WoundMaker™, and the methylcellulose clonogenic assay to assess clonogenic potential. The combination of ASA and OP with GEM significantly upended MiaPaCa-2 and PANC-1 pancreatic cancer cell viability, clonogenic potential, expression of critical extracellular matrix proteins, migration, and promoted apoptosis. ASA in combination with OP significantly improves the effectiveness of GEM in the treatment of pancreatic cancer and disables key survival pathways critical to disease progression.