Lack of chemopreventive effects of P2X7R inhibitors against pancreatic cancer

// Altaf Mohammed 1, 5 , Naveena B. Janakiram 1, 4 , Venkateshwar Madka 1 , Gopal Pathuri 1 , Qian Li 1 , Rebekah Ritchie 1 , Laura Biddick 1 , Hannah Kutche 1 , Yuting Zhang 1 , Anil Singh 1 , Hariprasad Gali 2 , Stan Lightfoot 1 , Vernon E. Steele 3 , Chen S. Suen 3 and Chinthalapally V. Rao 1, 4 1 Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology-Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 2 College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 3 Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA 4 VA Medical Center, Oklahoma City, OK, USA 5 Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA (Current address) Correspondence to: Chinthalapally V. Rao, email: cv-rao@ouhsc.edu Keywords: pancreatic cancer; chemoprevention; P2X7R; A438079; AZ10606120 Received: September 11, 2017      Accepted: October 11, 2017      Published: October 26, 2017 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 p48 Cre/+ -LSL-Kras G12D/+ 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 p48 Cre/+ -LSL-Kras G12D/+ mice. Following dose optimization studies, for chemoprevention efficacy, six-week-old p48 Cre/+ -LSL-Kras G12D/+ 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.