Activation of Par1 and Par2 Results in Calcium and Map Kinase Dependent Proliferation of Pancreatic Tumor Cells

Abstract

Background: The standard treatment for acute pancreatitis (AP) still remains based on supportive care. The searching for a drug that could alter the outcomes of this disease is a challenge. Some experimental studies report that previous inhibition of Cox-2 (the inflammatory isoform of cyclooxygenase) can ameliorate the histologic changes of the pancreas and the pulmonary lesion caused by systemic releasing of cytokines and others inflammatory mediators. The aim of this study is to evaluate the Cox-2 inhibition as a treatment for experimental acute pancreatitis. Material and Methods: Sixty Wistar male rats (240-260 g) were divided in two main groups: Group I (n = 30) -animals with taurocholate-induced acute pancreatitis treated with parecoxib (40 mg/Kg). Group II (n = 30) -animals with taurocholate-induced acute pancreatitis that received saline. AP was induced by retrograde injection of sodium taurocholate (2.5 %) into the main pancreatic duct. The Cox-inhibitor (parecoxib) was injected through penis dorsal vein immediately after AP induction. The parameters evaluated were histology, 72-hours mortality rate and serum levels of amylase, interleukin-10 (IL-10) and interleukin-6 (IL-6). Results: Serum levels of IL-6 and IL-10 were lower than in control group. Amylase serum levels and 72-hours mortality rate remained unchanged. Histologic evaluation was also unaltered, except for fat necrosis, which was worse in the parecoxib rats. Conclusion: Inhibition of Cox-2 might decrease the systemic release of at least two cytokines, but has a poor effect on mortality rate and on direct pancreas injury caused by taurocholate. .Purpose: In our previous communications, we reported the efficacy of genistein in augmenting the effects chemotherapeutic agents such as cisplatin and gemcitabine in pancreatic cancer cells in vitro (S.Banerjee et.al., APA-2004; AACR-2005). Here we report mechanism based evidence for the observed beneficial effect in vivo in SCID mice bearing orthotopically implanted pancreatic cancer cells. Background & Aims: Acute pancreatitis (AP) reflects the intensity of the inflammatory response and is divided into mild AP (MAP) or severe AP (SAP). Recent data suggests that genetic variation in functional gene polymorphisms of Glutathione S-Transferase theta-1 (GSTT-1*A) may help explain varying biological responses to AP. Our aim was to determine whether the GSTT-1*A polymorphism affects the severity of AP. Methods: 91 consecutive patients with AP (19 severe) and 268 controls were evaluated. The GSTT-1*A functional genotype was evaluated by polymerase chain reaction amplification, and restriction fragment length polymorphism.Results: The functional GSTT-1*A polymorphism was not significantly different in SAP (15 of 19; 78.9%) as compared to MAP (61 of 72; 84.7%; p = 0.54) and controls (228 of 268; 85.1%; p = 0.66). The functional GSTT-1*A genotype was not associated with elevated peak serum CRP (11.9 mg/dl vs 7.3 mg/dl; p = 0.19), IL-6 (74 vs 60; p = 0.9), APACHE II scores (7 vs 9; p = 0.26) or 48 hour Ranson sco...