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

Title
AMRI-59 functions as a radiosensitizer via peroxiredoxin I-targeted ROS accumulation and apoptotic cell death induction
Authors
Hong, Wan GiKim, Ju YeonCho, Jeong HyunHwang, Sang-GuSong, Jie-YoungLee, EunAhChang, Tong-ShinUm, Hong-DuckPark, Jong Kuk
Ewha Authors
창동신
SCOPUS Author ID
창동신scopus
Issue Date
2017
Journal Title
ONCOTARGET
ISSN
1949-2553JCR Link
Citation
ONCOTARGET vol. 8, no. 69, pp. 114050 - 114064
Keywords
peroxiredoxinradiosensitizerAMRI-59ROSnon-small cell lung cancer
Publisher
IMPACT JOURNALS LLC
Indexed
SCOPUS WOS scopus
Document Type
Article
Abstract
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 gamma-ionizing radiation (IR), followed by measurement of tumor volumes and apoptosis. The dose enhancement ratios of 30 mu M 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 gamma H2AX, 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/gamma H2AX/caspase pathway and suppression of ERK.
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DOI
10.18632/oncotarget.23114
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약학대학 > 약학과 > Journal papers
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