Abstract 1468: Cerium oxide nanoparticles sensitize pancreatic cancer cells to radiation by modulating the JNK pathway

Abstract

Abstract Pancreatic cancer, one of the most lethal cancers, has a poor prognosis and a high mortality rate. Currently, the absence of effective therapies increases reliance on radiation therapy (RT) to treat pancreatic cancer. We have previously reported that Cerium Oxide Nanoparticles (CONPs) are selectively toxic to cancer cells and possess the ability to selectively sensitize pancreatic cancer cells to radiation-induced cell death. Radiation-induced H2O2 production was significantly increased in the presence of less than or equal to 10 µM of CONPs and radiation-induced ROS production was increased in human L3.6pl pancreatic cancer cells pre-treated with 10 µM CONPs, which correlated with a significant decrease in cell viability and clonogenicity as compared to radiation alone. Conversely, ROS production was decreased in normal hTERT-HPNE pancreatic cells without impacting cell viability. The volume of pancreatic tumors was reduced by 48% in mice treated with combination therapy compared to radiation alone. Immunohistochemical (IHC) analysis revealed that combination therapy resulted in a significant increase in tumor cell apoptosis. In the most recent study, we determined the mechanism responsible for the increase in apoptosis as a result of increased ROS levels. L3.6pl cells (radiation sensitive), PANC-1 (radiation resistant) and HPNE (normal pancreatic cells) were treated with 5 Gy radiation in the presence or absence of 10 µM CONPs. CONPs selectively increased RT-induced Thioredoxin (TRX) oxidation in the cancer cells (L3.6pl: 14.2%, p<0.001; PANC-1: 23.5%, p<0.005) which correlated with a 35-40% increase in ASK-1 phosphorylation in both cell lines. Excitingly, western blot analyses showed a selective increase in JNK phosphorylation in both radiation sensitive (L3.6pl: JNK1 at 15%, JNK2 at 20%) and radiation resistant (PANC-1: JNK1 at 36%, JNK2 at 37%) cells which correlated with an increase in Caspase 3/7 activity (L3.6pl: 36.4%, p<0.05; PANC-1: 43.1%, p<0.05) compared to radiation alone. Knockdown of JNK expression by siRNA resulted in abrogation of Caspase 3/7 activity and corresponding cell death. Combination therapy of CONPs and radiation in an orthotopic murine model produced significant increases in JNK phosphorylation and Caspase 3 cleavage shown by IHC analysis. These data suggest that CONPs may act as a radiosensitizer in treatment of pancreatic cancer through the induction of JNK activation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1468. doi:1538-7445.AM2012-1468