Role of iron and TfR1 in the application of high‑dose ascorbate against pancreatic cancer

Pancreatic cancer remains one of the deadliest tumor diseases with an urgent need for new therapy options. At the same time, the use of high‑dose vitamin C in cancer treatment has been investigated for decades. Despite promising <i>in vitro</i> and <i>in vivo</i> data and initial clinical studies, there is a need for optimization with regard to an ideal treatment regimen and suitable patient population for the use of high‑dose vitamin C. The aim of the present study was to evaluate for the first time the combination of high‑dose vitamin C with the administration of iron in three human pancreatic cancer cell lines and to determine the exact cell death mechanism. While the investigated cell lines showed a high susceptibility to ascorbate treatment, the combination treatment with FeCl₃ generally led to a reduction in the ascorbate effect and in the formation of reactive oxygen species. The ascorbate‑induced cell death showed no signs of apoptosis but clear ferroptotic properties. Furthermore, treatment of the tumor cells with FeCl₃ was accompanied by reduced expression of TfR1, preventing an increase in the intracellular labile iron pool. The present study provided valuable information on the mechanism of action of high‑dose vitamin C in pancreatic cancer, whereby a combination treatment with ferric iron in the context of tumor therapy is not recommended based on these data.