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Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin i

Title
Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin i
Authors
Yang Y.J.Baek J.Y.Goo J.Shin Y.Park J.K.Jang J.Y.Wang S.B.Jeong W.Lee H.J.Um H.-D.Lee S.K.Choi Y.Rhee S.G.Chang T.-S.
Ewha Authors
이화정정우진창동신
SCOPUS Author ID
이화정scopus; 정우진scopus; 창동신scopus
Issue Date
2016
Journal Title
Antioxidants and Redox Signaling
ISSN
1523-0864JCR Link
Citation
vol. 24, no. 8, pp. 453 - 469
Publisher
Mary Ann Liebert Inc.
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
The intrinsic increase of reactive oxygen species (ROS) production in cancer cells after malignant transformation frequently induces redox adaptation, leading to enhanced antioxidant capacity. Peroxiredoxin I (PrxI), an enzyme responsible for eliminating hydrogen peroxide, has been found to be elevated in many types of cancer cells. Since overexpression of PrxI promoted cancer cells' survival and resistance to chemotherapy and radiotherapy, PrxI has been proposed as a therapeutic target for anticancer drugs. In this study, we aimed to investigate the anticancer efficacy of a small molecule inhibitor of PrxI. Results: By a high-throughput screening approach, we identified AMRI-59 as a potent inhibitor of PrxI. AMRI-59 increased cellular ROS, leading to the activation of both mitochondria-and apoptosis signal-regulated kinase-1-mediated signaling pathways, resulting in apoptosis of A549 human lung adenocarcinoma. AMRI-59 caused no significant changes in ROS level, proliferation, and apoptosis of PrxI-knockdown A549 cells by RNA interference. PrxI overexpression or N-acetylcysteine pretreatment abrogated AMRI-59-induced cytotoxicity in A549 cells. AMRI-59 rendered tumorigenic ovarian cells more susceptible to ROS-mediated death compared with nontumorigenic cells. Moreover, significant antitumor activity of AMRI-59 was observed in mouse tumor xenograft model implanted with A549 cells with no apparent acute toxicity. Innovation: This study offers preclinical proof-of-concept for AMRI-59, a lead small molecule inhibitor of PrxI, as an anticancer agent. Conclusions: Our results highlight a promising strategy for cancer therapy that preferentially eradicates cancer cells by targeting the PrxI-mediated redox-dependent survival pathways. © 2016 Mary Ann Liebert, Inc.
DOI
10.1089/ars.2014.6187
Appears in Collections:
약학대학 > 약학과 > Journal papers
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