Investigation of the effects of GW8510 pharmacological inhibitor on in vitro pancreatic cancer model

Pancreatic cancer is a disease characterized by high incidence and poor prognosis. Many patients with pancreatic cancer remain asymptomatic until the later stages of the disease. Currently, there is no effective treatment of the disease and it is known that survival time is very short even in patients who can be treated. It is seen that the development of new strategies to treat pancreatic cancer disease, is important and necessary. In this study, all genome gene expression microarray datas obtained from tissue samples taken from 176 pancreatic cancer patients in TCGA (The Cancer Genome Atlas) database and clinical findings of patients were evaluated. As a result of this evaluation, we showed that RRM2 gene which encodes the Ribonucleotide Reductase subunit M2 protein is highly expressed in patients with pancreatic cancer and it is statistically significant that this high expression correlates with low survival rate and poor prognosis in patients (p= 1.62e-4). In the literature review on inhibitors of RRM2, GW8510 has been found to have an inhibitory effect on RRM2 which is associated with poor prognosis and high mortality. This study was designed to investigate the therapeutic efficacy of GW8510 in pancreatic cancer since GW8510 molecule-mediated RRM2 inhibition, has not previously been shown in PANC-1 pancreatic cancer cells in the current literature. Cell viability analysis was performed by WST-8 method, and dosages in which two chemical agents show synergistic effects used in this study were determined by the CompuSyn combination analysis program. Apoptosis and cell cycle assays were performed using flow cytometry. The effect of GW8510 on the RRM2 protein levels was determined using the ELISA method. It was observed that the cell viability was inhibited 34 % in PANC-1 cells treated with 10 µM GW8510. When combination analysis was performed, it was determined that the combination of 10 µM GW8510 : 10 µM Gemcitabin showed synergistic interaction. t was found that this combination dose inhibited the migration of cells by 89.9%. In addition, the inhibitory effect of GW8510 agent on RRM2 protein levels in PANC-1 cells was shown for the first time with this thesis. The potential use of GW8510 in the treatment of pancreatic cancer through the inhibition of the RRM2 gene is promising. Further studies are needed to clarify the possible role of different metabolic pathways in the cytotoxic activity of GW8510 on pancreatic carcinoma cells.