Research Papers:

AMRI-59 functions as a radiosensitizer via peroxiredoxin I-targeted ROS accumulation and apoptotic cell death induction

Wan Gi Hong, Ju Yeon Kim, Jeong Hyun Cho, Sang-Gu Hwang, Jie-Young Song, EunAh Lee, Tong-Shin Chang, Hong-Duck Um and Jong Kuk Park _

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Oncotarget. 2017; 8:114050-114064. https://doi.org/10.18632/oncotarget.23114

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Wan Gi Hong1, Ju Yeon Kim1, Jeong Hyun Cho1, Sang-Gu Hwang1, Jie-Young Song1, EunAh Lee2, Tong-Shin Chang3, Hong-Duck Um1 and Jong Kuk Park1

1Division of Applied Radiation Bioscience, Korea Institute of Radiological and Medical Sciences, Seoul, Korea

2Impedance Imaging Research Center, Kyung Hee University, Seoul, Korea

3College of Pharmacy, Ewha Womans University, Seoul, Korea

Correspondence to:

Jong Kuk Park, email: [email protected]

Keywords: peroxiredoxin; radiosensitizer; AMRI-59; ROS; non-small cell lung cancer

Received: July 13, 2017    Accepted: November 26, 2017    Published: December 09, 2017


Previously, we identified AMRI-59 as a specific pharmaceutical inhibitor of peroxiredoxin (PRX) I enzyme activity. In this study, we examined whether AMRI-59 acts as a radiosensitizer in non-small cell lung cancer cells using clonogenic assays. The intracellular mechanisms underlying the radiosensitization effect of AMRI-59 were determined via immunoblotting in addition to measurement of ROS generation, mitochondrial potential and cell death. AMRI-59 activity in vivo was examined by co-treating nude mice with the compound and γ-ionizing radiation (IR), followed by measurement of tumor volumes and apoptosis. The dose enhancement ratios of 30 μM AMRI-59 in NCI-H460 and NCI-H1299 were 1.51 and 2.12, respectively. Combination of AMRI-59 with IR augmented ROS production and mitochondrial potential disruption via enhancement of PRX I oxidation, leading to increased expression of γH2AX, a DNA damage marker, and suppression of ERK phosphorylation, and finally, activation of caspase-3. Notably, inhibition of ROS production prevented ERK suppression, and blockage of ERK in combination with AMRI-59 and IR led to enhanced caspase-3 activation and apoptosis. In a xenograft assay using NCI-H460 and NCI-H1299, combined treatment with AMRI-59 and IR delayed tumor growth by 26.98 and 14.88 days, compared with controls, yielding enhancement factors of 1.73 and 1.37, respectively. Taken together, the results indicate that AMRI-59 functions as a PRX I-targeted radiosensitizer by inducing apoptosis through activation of the ROS/γH2AX/caspase pathway and suppression of ERK.

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