Anti-Cancer Activity of Acri fl avine as Metabolic Inhibitor of OXPHOS in Pancreas Cancer Xenografts

Purpose All currently available therapies for the treatment of pancreatic ductal adenocarcinoma (PDAC) show limited success. PDACs fast progression depends on the tumor characteristics and can be influenced by the microenvironment. The antibacterial drug acriflavine (ACF) has been shown to have anti-cancer activities in cell lines. Materials and Methods To understand the working mechanism of ACF on cancer progression and tumor-stromal interplay, we evaluated pancreatic cancer in cell culture (Panc-1) (morphology, cell invasion and RNA expression) and the macrophage cell line THP1 (representing innate immune stromal cells). In the translational arm, the activity of ACF on xenograft models of human PDAC tumors representing different clinical subclasses was investigated (tumor growth, morphology and immunofluorescence, RNA expression and pathway analysis). Results In vitro, ACF reduces epithelial-to-mesenchymal transition (EMT) and invasion of Panc-1 cells and shifts macrophage polarization to a M1-like anti-tumoral phenotype. At non-toxic concentrations, ACF downregulates cell metabolism. In xenografts, effect on tumor growth and metabolism could be confirmed; however, the innate immune stromal cells did not respond. Importantly, only in the moderately differentiated PDAC model, ACF could significantly suppress tumor growth and not in the fast-growing EMT-high model. Pathway analysis shows that ACF highly significantly downregulates metabolic pathways, especially OXPHOS and MYC/cell proliferation pathways in xenografts. Conclusion ACF, with known pleiotropic effects on cancer cells, is in this study shown to be an attractive therapeutic based on its novel observed metabolic activity. Repurposing this compound for cancer treatment should be in the setting with other targeting agents, which offers reduced chance of resistance development in PDAC. Further evaluation should best be done in biological complex models such as human xenografts or syngeneic cancer models.

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