Abstract 5853: Peroxiredoxin I-targeted AMRI-59 has a role of radiosensitizer by promoting induction of ROS/γH2AX/caspase pathway and suppression of ERK

We have identified AMRI-59, one of small molecule, is specific pharmaceutical inhibitor of peroxiredoxin (PRX) I enzyme activity in our previous study. In this study, we tried to prove whether AMRI-59 has role of radiosensitizer against non-small cell lung cancer cells - NCI-H460 and NCI-H1299. The radiosensitizer effects of AMRI-59 were tested with clonogenic assays. The intracellular mechanism underlying this effect was determined by performing immunoblotting and measuring ROS generation, mitochondrial potential and cell death. The radiosensitizer activity of AMRI-59 in vivo was tested in nude mice by treating with AMRI-59 and IR, and measuring tumor volume and assessing apoptosis. Dose-enhancement ratios of 30 μM AMRI-59 in NCI-H460 and NCI-H1299 are 1.57 or 3.38, respectively. Combination with AMRI-59 and IR also increased the production of ROS and disruption of mitochondrial potential via enhancement of PrxI oxidation, which subsequently induced one of DNA damage markers - phospho-γH2AX, and suppressed phosphorylation of ERK, and, finally, activated caspase-3. Notably, inhibition of ROS production prevented ERK suppression, and inhibition of ERK in addition of combination with AMRI-59 and IR increased caspase activation and apoptosis. In a xenograft assay, combination with AMRI-59 and IR delayed tumor growth by 11.4 days compared with controls, yielding an enhancement factor of 1.48. Collectively, these results indicate that AMRI-59 functions as a Prx I - targeted radiosensitizer by induction of apoptosis through activation of a ROS/γH2AX/caspase pathway and suppression of ERK. Citation Format: Wan Gi Hong, Jeong Hyun Cho, Ju Yeon Kim, EunAh Lee, Sang-Gu Hwang, Tong-Shin Chang, Hong-Duck Um, Jong Kuk Park. Peroxiredoxin I-targeted AMRI-59 has a role of radiosensitizer by promoting induction of ROS/γH2AX/caspase pathway and suppression of ERK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5853. doi:10.1158/1538-7445.AM2017-5853