Pancreatic cancer is one of the most aggressive cancer due to the late diagnosis and failure to respond to the treatment despite advances in tumor biology and the development of new cancer therapeutic strategies. It has been reported that these characteristics of pancreatic cancer originate from cancer stem cells within the tumor mass. It has also been reported that Fentanyl is a fast-acting analgesic that binds to the mu-opioid receptors and some other mu-opioid receptors are involved in this cancer process. In this study, we determined the effect of Fentanyl on PANC-1 cells, by assessing the gene expression of cancer stem cell marker genes (Nanog, Oct4, and Sox2) and apoptosis-related genes (BAD, Bax, Bcl-2, and p53) by Quantitative RealTime PCR. The number of cancer stem cells was determined by Flow Cytometry. The results of our study showed that Fentanyl administration decreased the number of cancer and cancer stem cells in the PANC-1 cell population, decreased the gene expression of stem cell marker and increased the expression of apoptosis-related genes. These results indicate that Fentanyl, which is used routinely in the pain palliation of pancreatic cancer, can be considered as an option in the treatment of pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumors of the pancreas. Preclinical studies show that it evades the immune system with immune checkpoints and promotes tumor development. V-domain Ig suppressor of T cell activation (VISTA) is a new immunecheck point from the B7 family and is highly expressed in cancer cells. Overexpression of toll like receptor 4 (TLR4) in pancreatic adenocarcinoma is associated with inducing tumorigenesis, tumor growth and resistance to chemotherapy. Naloxone is an opioid and inhibits TLR4-ligand association. In this study, we investigated the connection of TLR4 and downstream pathway with immune-check point VISTA in pancreatic cancer proliferation. We rst collected pancreatic cancer-related datasets using the GEPIA2 and UALCAN databases. Based on the data obtained the effect of different concentrations and incubation times of Naloxone were used on PANC-1 cells proliferation. Combination of Naloxone and VISTA-siRNA were applied, and effect of both Naloxone and combined reatment on TLR4, Interleukin 1 receptor associated kinase 4 (IRAK4) and VISTA gene expression were analysed in pancreatic cancer cells. As a result of analysis with Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), gene expression levels of TLR4, IRAK4 and VISTA were signi cantly suppressed and cell proliferation was signi cantly reduced. We found that administration of Naloxone and VISTA-siRNA in combination to PDAC cells suppressed signaling. Therefore, we considered that the relationship between VISTA and TLR4 signaling pathways and the other possible associated signal molecules may be an important marker in determining the response of immune checkpoint inhibitors in cancer treatment.
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