Zinc-related Treatments Combined with Chloroquine and Gemcitabine for Treating Pancreatic Cancer

Pancreatic cancer is one of the deadliest cancers, with a 10% 5-year survival rate. A prominent issue with the treatment mainly used today, gemcitabine, is that it is unable to penetrate the stroma around the pancreatic cancer tumor. The stroma is a dense network of cells that promotes cancer development and metastasis and creates difficulty for chemotherapy treatments to be delivered effectively to the tumor. Targeting the pathways responsible for both the stroma (namely the Hedgehog signaling pathway) and the tumor (the Ras/MAPK pathway) could potentially lead to more effective treatments. The dysregulation of zinc has been implicated in disease progression through these pathways, however its exact effect is unclear. TPEN is a metal ion chelator that is able to induce zinc deficiency. We hypothesized that if various dosages of TPEN and zinc are used in combination with Chloroquine and Gemcitabine, then combinations of medium to high doses of zinc, Chloroquine, and Gemcitabine will be the most effective at reducing cell proliferation. Several treatment combinations were created in a drug matrix and tested using a cell proliferation assay. To mimic the stroma-tumor interaction that would occur in vivo, we took the conditioned medium from pancreatic cancer associated fibroblasts (mCAF) and cultured pancreatic cancer cells (PANC-1). The results showed that while TPEN was able to significantly lower cell proliferation, it was not more effective than the current treatment. However, when combined with Chloroquine and Gemcitabine, zinc and TPEN both significantly lowered cell proliferation compared to Gemcitabine, suggesting a synergistic effect that resulted in a more cytotoxic treatment. Further research and clinical trials on this topic are needed to determine whether this could be a viable treatment for pancreatic cancer. This repurposed treatment could potentially increase survival rates and become a more affordable alternative to novel drug development.