Epithelial-Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Neoadjuvant chemotherapy (NAC) has become a standard treatment for patients scheduled for surgical resection, but the high rate of postoperative recurrence is a critical problem. Optimization of NAC is desirable to reduce postoperative recurrence and achieve long-term survival. However, if a patient's general condition deteriorates due to NAC toxicity, surgical outcomes may be compromised. Therefore, we aimed to identify drug(s) that can be used in combination with gemcitabine (GEM), a drug widely used for the treatment of PDAC, to inhibit distant metastatic recurrence, particularly after surgery. After several screening steps, ML210, a low molecular weight chemical, was found to suppress the epithelial-mesenchymal transition (EMT) in PDAC cells in combination with GEM. Specifically, low dose ML210 in combination with GEM was sufficient for cell migration without apparent toxicity or cell death. Mechanistically, ML210, which was developed as a glutathione peroxidase 4 (GPX4) inhibitor to induce lipid peroxidation, increased the oxidized lipid concentrations in PDAC cells. The oxidization of the cell membrane lipids may suppress EMT, including cell migration. Since EMT is a major malignant phenotype of PDAC, our findings may lead to the advancement of PDAC therapy, especially in the prevention of postoperative recurrence.