Abstract
Pancreatic cancer (PC) is an almost uniformly lethal disease with inflammation playing an important role in its progression. Sustained stimulation of purinergic receptor P2X7 drives induction of NLRP inflammasome activation. To understand the role of P2X7 receptor and inflammasome, we performed transcriptomic analysis of p48Cre/+-LSL-KrasG12D/+ mice pancreatic tumors by next generation sequencing. Results showed that P2X7R's key inflammasome components, IL-1β and caspase-1 are highly expressed (p < 0.05) in pancreatic tumors. Hence, to target P2X7R, we tested effects of two P2X7R antagonists, A438079 and AZ10606120, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PC in p48Cre/+-LSL-KrasG12D/+ mice. Following dose optimization studies, for chemoprevention efficacy, six-week-old p48Cre/+-LSL-KrasG12D/+ mice (24–36/group) were fed modified AIN-76A diets containing 0, 50 or 100 ppm A438079 and AZ10606120 for 38 weeks. Pancreata were collected, weighed, and evaluated for PanINs and PDAC. Control diet-fed male mice showed 50% PDAC incidence. Dietary A438079 and AZ10606120 showed 60% PDAC incidence. A marginal increase of PanIN 3 (carcinoma in-situ) was observed in drug-treated mice. Importantly, the carcinoma spread in untreated mice was 24% compared to 43–53% in treatment groups. Reduced survival rates were observed in mice exposed to P2X7R inhibitors. Both drugs showed a decrease in caspase-3, caspase-1, p21 and Cdc25c. Dietary A438079 showed modest inhibition of P2X7R, NLRP3, and IL-33, whereas AZ10606120 had no effects. In summary, targeting the P2X7R pathway by A438079 and AZ10606120 failed to show chemopreventive effects against PC and slightly enhanced PanIN progression to PDAC. Hence, caution is needed while treating high-risk individuals with P2X7R inhibitors.
Highlights
Pancreatic cancer (PC) still remains a devastating disease that is almost uniformly lethal
Our results show that P2X7 receptor (P2X7R) (~20-fold) (Figure 1A), its key inflammasome components: caspase-1 (15-fold) (Figure 1B), IL-1β (~45-fold) (Figure 1C), and in addition to IL-18 (~35-fold), IL-33 (~93 folds), TNF-α (~13-fold) and COX-2 (~41-fold) are increased in pancreatic tumors compared to normal pancreas
We synthesized P2X7R inhibitors A438079 and AZ10606120 for the MTD and chemoprevention efficacy studies from the procedures described in previous publications and the patent application filed by Jones, et al (PCT International Publication Number WO 2009/106564 A2) (Figure 2A–2B)
Summary
Pancreatic cancer (PC) still remains a devastating disease that is almost uniformly lethal. Over 53,000 individuals will be diagnosed, with >43,000 deaths expected in the US alone in 2017 [1]. Since 2004, the rates of pancreatic cancer have increased by 1.5% per year [1]. Pancreatic cancer accounts for about 3% of all cancers in the US and about 7% of all cancer deaths [1]. Pancreatic Intraepithelial Neoplasia (PanIN) are the most common precursors to invasive pancreatic ductal adenocarcinoma (PDAC), rendering them promising targets for intervention, especially in the high-risk population as it takes several years for PanIN progression into ductal adenocarcinoma and acquire metastatic capacity [2,3,4,5]. Chronic inflammation is a hallmark of many diseases, including PC and pancreatitis [6]. The etiology of PC and laboratory investigations have demonstrated that inflammation represents an important role in its carcinogenesis [6,7,8,9,10,11]
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