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Pyrvinium Pamoate Alone and With Gemcitabine Exhibits Anti-Pancreatic Cancer Activity in 2D and 3D Cell Culture
Karabo Serala1, Jinming Bai1, Sharon Prince1
1Department of Human Biology, University of Cape Town, Observatory, Cape Town, South Africa.
Abstract:
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.
Insights
Pyrvinium pamoate shows promise in treating pancreatic cancer by killing cancer cells and stopping their spread. It also works effectively with gemcitabine, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Pancreatic cancer has a poor prognosis with limited effective treatments.
- Drug repurposing is a valuable strategy for discovering new anti-cancer agents.
- Pyrvinium pamoate, an antihelminthic drug, has emerged as a potential pancreatic cancer therapeutic.
Purpose of the Study:
- To investigate the anti-cancer effects and mechanisms of pyrvinium pamoate in pancreatic cancer.
- To evaluate the synergistic potential of pyrvinium pamoate in combination with gemcitabine.
Main Methods:
- Utilized 2D cell cultures and 3D spheroids of pancreatic cancer.
- Assessed cytotoxicity, epithelial-to-mesenchymal transition (EMT), invasion, and migration.
- Analyzed DNA damage, stemness markers, cell cycle, and cell death pathways (apoptosis, autophagy).
- Evaluated drug synergy using established pancreatic cancer models.
Main Results:
- Pyrvinium pamoate demonstrated significant short- and long-term cytotoxicity.
- The drug inhibited EMT, invasion, and migration, while inducing DNA damage and cell cycle arrest.
- Pyrvinium pamoate suppressed stemness markers and the PI3K/AKT pathway, leading to apoptosis and autophagy.
- A synergistic effect was observed when pyrvinium pamoate was combined with gemcitabine.
Conclusions:
- Pyrvinium pamoate exhibits multifaceted anti-pancreatic cancer activity, extending beyond mitochondrial inhibition.
- The drug effectively reduces cancer cell proliferation, invasion, and migration.
- Pyrvinium pamoate shows significant therapeutic potential as a single agent and in combination with gemcitabine for pancreatic cancer treatment.
