<p>Anti-Cancer Activity of Acriflavine as Metabolic Inhibitor of OXPHOS in Pancreas Cancer Xenografts</p>

Abstract

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.

Glucose Metabolism: The Metabolic Signature of Tumor Associated Macrophage

“…Similarly, FAO inhibitors are developed to achieve the phenotypic transition of macrophages and inhibit tumor development. Furthermore, researchers have revealed that acriflavine (ACF), a heteroaromatic dye with an antibacterial and antiviral effect, shifted macrophage polarization to an M1-like anti-tumoral phenotype by blocking the HIF-1α pathway and enhancing glucose uptake in PDAC ( 94 ). This phenomenon shows that increasing the glucose utilization of TAMs may be a promising direction.…”

The Activation of the Tumor Suppressor Protein p53 by Acriflavine Leads to Mitochondrial Dysfunction and Improves the Radiosensitivity of Colon Cancer Cells

“…Acriflavine (ACF) is a mixture of 3, 6-diamino-10methyl acridine (trypaflavine) and 3, 6-diamino-acridine (proflavine), which has been used as a preservative and wound healing agent [6]. It has been revealed that ACF can inhibit many cancers, including osteosarcoma, breast cancer, brain cancer, lung cancer, liver cancer, and pancreatic cancer [7][8][9][10][11]. ACF can also act on AIDS patients as an antiviral drug without major side effects [12].…”

Development and Optimization of Acriflavine-Loaded Polycaprolactone Nanoparticles Using Box–Behnken Design for Burn Wound Healing Applications

“…Acriflavine is also known for its fluorescent nature in confocal laser scanning microscopy studies [ 14 ]. It can also be used to inhibit vascularization, tumor growth factors, and HIF-I dimerization [ 15 , 16 ]. It can be used against E-coli and drug-resistant staphylococcus aureus [ 17 ].…”