The Antitumor Activity of Sodium Selenite Alone and in Combination with Gemcitabine in Pancreatic Cancer: An In Vitro and In Vivo Study

Simple Summary The treatment of advanced pancreatic cancer represents a major challenge because of its chemoresistance and low survival rate. The aim of this research is to test a new antitumor agent (sodium selenite) in pancreatic cancer, both in vitro and in vivo, focusing on the molecular mechanisms involved and its combination with traditional chemotherapy (gemcitabine). Our results show that selenite has a strong antitumor effect against pancreatic cancer, via parthanatos cell death, and enhances the effect of gemcitabine via the p38 pathway in both in vitro and in vivo assays. These results could improve the outcome of pancreatic cancer patients and could be the start of future clinical trials. Sodium selenite acts by depleting enzymes that protect against cellular oxidative stress. To determine its effect alone or in combination with gemcitabine (GMZ) in pancreatic cancer, we used PANC-1 and Pan02 cell lines and C57BL mice bearing a Pan02-generated tumor. Our results demonstrated a significant inhibition of pancreatic cancer cell viability with the use of sodium selenite alone and a synergistic effect when associated with GMZ. The molecular mechanisms of the antitumor effect of sodium selenite alone involved apoptosis-inducing factor (AIF) and the expression of phospho-p38 in the combined therapy. In addition, sodium selenite alone and in association with GMZ significantly decreased the migration capacity and colony-forming ability, reduced tumor activity in multicellular tumor spheroids (MTS) and decreased sphere formation of cancer stem cells. In vivo studies demonstrated that combined therapy not only inhibited tumor growth (65%) compared to the untreated group but also relative to sodium selenite or GMZ used as monotherapy (up to 40%), increasing mice survival. These results were supported by the analysis of C57BL/6 albino mice bearing a Pan02-generated tumor, using the IVIS system. In conclusion, our results showed that sodium selenite is a potential agent for the improvement in the treatment of pancreatic cancer and should be considered for future human clinical trials.