Inhibitory Effect Of Ethyl Pyruvate On The Human Pancreatic Carcinoma Cell Line

Background Pancreatic cancer has the poorest prognosis and is usually occult in onset. Local regional and lymphatic and hematogenous metastasis have been of occurrence in 80 percent of pancreatic cancer patients as they are diagnosed, who have missed the chance of operation. Chemotherapy remains is an important method of treatment pancreatic cancer, although its curative effect is poorly. Resistance phenomena, especially acquired drug-resistance, have been severely hampering the applications of chemotherapeutics during chemotherapy of tumor. The anti-tumor chemotherapeutic drugs, such as 5-florouracil (5-FU) and so on, have had major adverse reaction and resistance phenomena, which hampered its applications in clinic. So it is important that exploitation of anti-tumor drugs of improving effect and decreasing toxicity or substitution. High mobility group protein B1 (HMGB1) HMGB1, an important late inflammation factor, is abundantly expressed in blast and malignant cells, which is a germane chromosomal proteins with axons prolongation and tumor growth and soakage or metastasis. HMGB1 is up-regulated protein in gastrointestinal stromal tumors, prostatic carcinoma, mammary cancer, small cell lung cancer and the other tumor tissues, and there was significantly positive correlation between its expressed level and prognosis of sufferer and tumor metastasis. Pancreatic cancer could invade neighboring organs, lympha, vascellum and neuroplexus, and diffusions along neuroplexus is its especially transfer. HMGB1 is important in soakage and transfer of pancreatic cells, which could urge the decomposition of the extracellular matrix, accelerate the soakage and transfer of pancreatic carcinoma. HMGB1 is a ligand for the receptor for RAGE. HMGB1-RAGE signaling triggers activation of key cell signaling pathways, such as NF-кβ, p38MAKE, JNK, p42/p44MAPK and Rac/Cdc42, thereby causing the activation of matrix metalloproteinase MMP-2 and MMP-9; Blockade of the HMGB1-RAGE interaction can suppress activation of p44/p42, p38 MAKE, and SAP/JNK MAPK kinase and inhibition of migration of glioma, forcing the tumor to undergo prolonged dormancy with decreased proliferation, invasion, and matrix metalloproteinase (MMP) activity. So HMGB1 inhibitor may be potential curative of curing and preventing invasion and transfer of pancreatic cancer. Nowadays, there were major three HMGB1 inhibitors, for example anti-HMGB1-body, A box, ethyl pyruvate (EP). Ethyl pyruvate, a stable aliphatic ester derived from pyruvic acid, has effect of anti-inflammatory and immunoregulation. Ethyl pyruvate inhibits the release of TNF and HMGB1 from endotoxin-stimulated RAW 264.7 murine macrophages, as well as attenuates activation of both the p38 mitogen-activated protein kinase and NF-кβsignaling pathways. In this study, I investigate the effect of inhibiting of EP and 5-FU on PANC-1/AsPC-1 cell line, so as to provide theoretically and experimental bases for prevention and therapy of pancreatic cancer.Objective To investigate the influence of ethyl pyruvate (EP) alone and in combination with 5-Fluorouracil (5-FU) on proliferation and apoptosis of human pancreatic carcinoma cell lines PANC-1/AsPC-1 and expression of high mobility group protein B1 (HMGB1).Methods The effects of EP and 5-FU alone or 5-FU combined with EP (EP group, E group; 5-FU group, F group; EP combined with 5-FU group, EF group) on the proliferation of pancreatic cancer cell line PANC-1/AsPC-1 was measured by MTT test; Apoptosis ratio was measured by flow cytometry (FCM). The HMGB1 mRNA expression level on pancreatic carcinoma cell line PANC-1/AsPC-1 in every medication group was determined by Real time PCR (RT-PCR).Results The cell proliferation was inhibitory after being treated with each medication group(P<0.05), and cell inhibitory rations were higher in EF groups than F groups(P<0.05). The proliferation of pancreatic carcinoma cell was inhibitory after being treated with E0.5225F10/E1.0450F20/E2.0900F40/E3.1350F80 combined therapy groups compared with E groups (P<0.05), and the cell inhibitory rations were higher in E0.5225/E1.0450/E2.0900/E3.1350 single therapy groups than controlled F groups(P<0.05). EF groups compared with E groups, apoptosis ratios of the pancreatic cancer cell were raised; apoptosis ratios of pancreatic cancer cell were higher in E groups than F groups (P<0.05). HMGB1 mRNA expression levels were degraded after being treated with E3.1350F80/E4.1800F160 combined therapy groups compared with controlled E groups (P<0.05), and HMGB1 mRNA expression levels were lower in E3.1350/E41800 single therapy groups than controlled F groups in pancreatic cancer cell lines (P<0.05).Conclusions EP could inhibit cell proliferation and induce cell apoptosis by the inhibition of HMGB1 expression on pancreatic carcinoma cells, thus, EP have the effect of anti-pancreatic carcinoma, but the concrete mechanism and the effect in vivo need further lucubrate.