thetic Triterpenoids Prolong Survival in a Transgenic Pr R se Model of Pancreatic Cancer

wnloaded creatic cancer is the fourth leading cause of cancer-related deaths in the United States and is nearly s fatal. Whereas early detection offers the most promising approach for reducing the mortality of isease, there is still a need to develop effective drugs for the prevention and treatment of pancreatic r. We tested two promising classes of noncytotoxic drugs, synthetic oleanane triterpenoids and ids, for the prevention of carcinogenesis in the highly relevant LSL-Kras;LSL-Trp53; Cre (KPC) mouse model of pancreatic cancer. KPC transgenic mice closely recapitulate the genetic ions, clinical symptoms, and histopathology found in human pancreatic cancer. Beginning at ks of age, mice were fed powdered control diet or a diet containing the triterpenoids CDDO-methyl CDDO-Me) or CDDO-ethyl amide, the rexinoid LG100268 (LG268), or the combination, until the isplayed overt symptoms of pancreatic cancer. CDDO-Me, LG268, the combination of CDDO-Me G268, and the combination of CDDO-ethyl amide and LG268, all significantly (P < 0.05) increased al in the KPC mice by 3 to 4 weeks. Recent studies have shown that gemcitabine, the current rd of care for human pancreatic cancer, does not extend survival in KPC mice. In cell lines develfrom the KPC mice, the triterpenoids directly interact with both signal transducer and activator of ription 3 and IκB kinase (IKK) to decrease constitutive interleukin-6 secretion, inhibit constitutive transducer and activator of transcription 3 phosphorylation, and block the degradation of IκBα signal when challenged with tumor necrosis factor α. These results suggest that oleanane triterpenoids and rexinoids have the potential to prevent pancreatic cancer. Cancer Prev Res; 3(11); OF1–8. ©2010 AACR.