Vortioxetine enhances the anti-pancreatic cancer efficacy of gemcitabine through reducing MAOB expression.

INTRODUCTION: Pancreatic cancer is a highly aggressive malignancy with a poor prognosis, largely owing to chemoresistance and frequent recurrence following gemcitabine-based therapy. This study investigated whether vortioxetine, a multimodal serotonin (5-HT) modulator, could enhance the antitumor efficacy of gemcitabine and explored the underlying molecular mechanisms. METHODS: The effects of vortioxetine alone and in combination with gemcitabine were evaluated in pancreatic cancer cells and xenograft models. Cell proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) were assessed using functional assays and relevant molecular markers. RNA sequencing was performed to identify potential molecular targets of vortioxetine, followed by molecular docking, thermal stability assays, and gene knockdown experiments for mechanistic validation. RESULTS: Vortioxetine significantly enhanced the inhibitory effects of gemcitabine on pancreatic cancer cell proliferation in vitro and tumor growth in xenograft models. The combination treatment markedly promoted apoptosis, as indicated by increased levels of cleaved poly(ADP-ribose) polymerase (PARP) and cleaved caspase-3. It also suppressed cancer cell migration and invasion and reversed EMT-related changes, as demonstrated by the upregulation of E-cadherin and downregulation of N-cadherin and Snail. RNA sequencing identified monoamine oxidase B (MAOB; EC 1.4.3.4) as a potential molecular target associated with vortioxetine treatment, which was further supported by molecular docking and thermal stability assays. Moreover, MAOB knockdown phenocopied the effects of vortioxetine by enhancing gemcitabine sensitivity and suppressing EMT-associated phenotypes. DISCUSSION: Vortioxetine potentiates the antitumor efficacy of gemcitabine against pancreatic cancer, with its effects associated with reduced MAOB expression, enhanced apoptosis, and suppression of EMT. These findings support further investigation of vortioxetine combined with gemcitabine as a potential therapeutic strategy for overcoming chemoresistance in pancreatic cancer.