Introduction:Oncogenic aaivation of the K-ras gene occurs in >90%of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy.Increase of reactive oxygen species(ROS) has also been observed in a wide spectrum of cancers.This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer.Methods:ROS level,NADPH oxidase(NOX) aaivity and expression,and cell invasion were examined in human pancreatic dua epithelial E6E7 cells transfeaed with K-ras~(G12V) compared with parental E6E7 cells.The cytotoxic effea and antitumor effect of capsaicin,a NOX inhibitor,were also tested in vitro and in vivo.Results:K-ras transfeaion caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3’-kinase(PI3K) pathway.Importantly,capsaicin preferentially inhibited the enzyme aaivity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells.Furthermore,capsaicin effeaively inhibited cell proliferation,prevented invasiveness of /(-ras-transformed pancreatic cancer cells,and caused minimum toxicity to parental E6E7 cells.In vivo,capsaicin exhibited antitumor aaivity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells.Conclusions:K-ras oncogenic signaling causes increased ROS stress through NOX,and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors.Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism. Introduction: Oncogenic aa of the K-ras gene occurs in> 90% of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy. Crease of reactive oxygen species (ROS) has also been observed in a wide spectrum of cancers. This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer. Methods: ROS level, NADPH oxidase (NOX) aaivity and expression, and cell invasion were examined in human pancreatic dua epithelial E6E7 cells transfeed with K-ras ~ (G12V) compared with parental E6E7 cells.The cytotoxic effea and antitumor effect of capsaicin, a NOX inhibitor, also also tested in vitro and in vivo. Results: K-ras transfeaion caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3’-kinase (PI3K) pathway. Implantantly, capsaicin preferentially inhibited the enzyme aaivity of NOX and induced se vere ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells. Frther and capsaicin effeaively inhibited cell proliferation, prevented invasiveness of / (- ras-transformed pancreatic cancer cells, and caused minimum toxicity to parental E6E7 cells. In vivo, capsaicin exhibited antitumor aaivity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells. Conclusions: K-ras oncogenic signaling induced increased ROS stress through NOX, and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors. Our study provides a basis for developing a novel therapeutic strategy to kill K-ras-transformed cells through a redox-mediated mechanism.