Pyrvinium Pamoate Alone and With Gemcitabine Exhibits Anti‐Pancreatic Cancer Activity in <scp>2D</scp> and <scp>3D</scp> Cell Culture Models

Pancreatic cancer is an intractable disease with the worst prognosis of all common cancers. The treatment regimens currently used for pancreatic cancer do not significantly impact patient survival, and therefore, effective treatment strategies are urgently needed. Drug repurposing, which identifies new indications for existing and approved drugs, has proven to be a desirable approach to anti-cancer drug discovery. Indeed, the antihelminthic drug, pyrvinium pamoate, has shown promise as an anti-pancreatic cancer drug. However, the only mechanism of action ascribed to this has been its ability to inhibit mitochondrial function. This study showed, using pancreatic cancer 2D cell cultures and 3D spheroids, that pyrvinium pamoate exhibited short- and long-term cytotoxicity, inhibited epithelial-to-mesenchymal transition and cell invasion and migration. Mechanistically, pyrvinium pamoate induced DNA damage, inhibited stemness markers and the PI3K/AKT cell survival pathway, triggered an S-phase cell cycle arrest and induced apoptotic and autophagic cell death. Importantly, pyrvinium pamoate acted synergistically with the first-line drug, gemcitabine, in 2D and 3D pancreatic cancer cell culture models. This study provides evidence that pyrvinium pamoate is effective as a single agent and in combination with gemcitabine for the treatment of pancreatic cancer.