PH‐427 reduces the survival of fat‐treated pancreatic cancer cells

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal cancer. A large number of epidemiological studies have linked type‐2 diabetes, obesity and metabolic syndrome, characterized by insulin resistance with an increased risk for developing PDAC. The IGF‐IR/PI3K/AKT survival pathway has been suggested to be the major signaling pathway involved in these processes. Indeed, AKT is a key signaling pathway in PDAC as it mediates cancer cell survival and proliferation. We have developed the AKT Pleckstrin Homology (PH) domain inhibitor, PH‐427, which prevents AKT activation and possess anti‐tumor activities in vivo models of pancreatic cancer. Hence, the objectives of this study were 1) to develop a cellular model for obesity‐driven pancreatic cancer and 2) to determine the effects of PH‐427 on cell viability of pancreatic cancer cells exposed to a fatty environment. BxPC3 cells were incubated in RPMI media supplemented with cholesteryl hemisuccinate (CHS) for two weeks. We show that CHS induced an insulin resistance state whereby AKT phosphorylation is reduced upon IGF‐I stimulation as compared to control cells. Moreover, MTT assays indicated that CHS‐treated cells were more sensitive to PH‐427 treatment as compared to control cells (IC50= 10.9±3.7 versus 15.2±1.5□M). These preliminary data suggest the promising potential use of this novel drug for the treatment of obesity‐induced PDAC.Grant Funding Source : None