Therapeutic Effects Of P38 MAPK Inhibitor In Diabetic Pancreatic Cancer Models

Part ? The Effects of P38 MAPK Inhibitor on The Biological Behavior of Pancreatic Tumor Cells under High Glucose ConditionObjective The aim of this study was to investigate whether p38 MAPK inhibitor could reverse the effects of high glucose induced the expression of p38 MAPK,epithelial-mesenchymal transition makers and inflammatory factors of pancreatic tumor cells.Materials and Methods Panc02 and Colo357 cell lines were cultured with different concentration of glucose.SB 203580(10?mol/L)were added to the medium with high glucose.The effects of high glucose(25mmol/L,HG)on the biological behavior of pancreatic tumor cells were characterized by MTT assays,flow cytometry analysis,cell migration and invasion,morphology,immunofluorescent staining and Western Blot assays.Results Glucose does-dependently increased the phosphorylation of p38 MAPK and time-dependently increased the proliferation of pancreatic cancer cells which were both significantly reduced by SB203580.SB203580 induced signifcant apoptosis in tumor cells cultured in an HG environment,and inhibited both HG and TGF-? induced tumor cell migration and invasion.Both TGF-P and HG reduced E-cadherin expression and increased vimentin expression,thereby inducing EMT in tumor cells.The expression of TNF-?,IL-6 and phospho-NFKB(p-NF?B)gradually increased in tumor cells that were treated with increasing concentrations of glucose;meanwhile,SB203580 signifcantly suppressed the expression of inflammatory factors under the HG condition,indicating that HG induced inflammatory factor activation through the p38 MAPK pathway.Conclusion HG increased p38 MAPK phosphorylation in pancreatic tumor cells while simultaneously enhancing the proliferative,anti-apoptotic,invasive and migratory capabilities of the cells.SB203580 suppressed the HG-induced proliferation,invasion,migration,EMT and inflammatory factors of tumor cells.Moreover,inflammatory factor inhibitors also suppressed EMT,indicated that p38 MAPK induced EMT progression through increasing the expression of inflammatory factors.Part ? Therapeutic Effects of P38 MAPK Inhibitor in Diabetic Pancreatic Cancer ModelsObjective The aim of this study was to investigate the therapeutic effects of p38 MAPK inhibitor administration on diabetic pancreatic cancer outcomes.Materials and Methods C57BL/6 mice were intra-peritoneally administered with streptozotocin(25mg/kg/day)for 5 days and then fed with high fat diet in following 3 weeks to establish animal models of type 2 diabetes.p38 MAPK inhibitor,SB203580,was intravenously injected into pancreatic cancer mice for 7 consecutive days after surgical orthotopic implantation.The orthotopically implanted tumors in wild-type controls and diabetic mice treated with SB203580 or saline were monitored by MRI in 1,2,3 and 4 weeks.The 30-day survival was assessed by Kaplan-Meier survival analysis.Western Blot assays and immumohistochemical staining were performed to investigate the expression p38 MAPK,EMT makers and inflammatory factors of on day 30.Results Survival curves showed that SB203580 could significantly increase the survival of diabetic(P=0.011)and non-diabetic(P=0.042)pancreatic cancer mice.Tumor volume measurement by MRI showed that the diabetic cancers grew much more rapidly than non-diabetic controls,while SB203580 treatment significantly suppressed the tumor growth both in non-diabetic and diabetic mice.In addition,Western blot analysis of tumors showed that diabetes decreased the expression of E-cadherin while increased the expression of vimentin;however,SB203580 treatment could reverse the above EMT process.Furthermore,the pro-infammatory factors(IL-6,TNF-a,NF?B)in diabetic pancreatic tumors were significantly reduced in SB203580-treated groups.Conclusion Diabetes induced the phosphorylation of p38 MAPK and inflammation,which promoted the proliferation and EMT-mediated metastasis of pancreatic cancer;while SB203580 suppressed the diabetes-induced tumor growth and metastasis,which might have been caused by suppression of EMT and inflammation.