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

Yeon Ju Yang, Jin Young Baek, Jail Goo, Yoonho Shin, Jong Kuk Park, Ji Yong Jang, Su Bin Wang, Woojin Jeong, Hwa Jeong Lee, Hong Duck Um, Sang Kook Lee, Yongseok Choi, Sue Goo Rhee, Tong Shin Chang

Research output: Contribution to journalArticle

23 Citations (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.

Original languageEnglish
Pages (from-to)453-469
Number of pages17
JournalAntioxidants and Redox Signaling
Volume24
Issue number8
DOIs
Publication statusPublished - 2016 Mar 10

Fingerprint

Peroxiredoxins
Reactive Oxygen Species
Cells
Neoplasms
Apoptosis
Oxidation-Reduction
Mitochondria
Molecules
Chemotherapy
Radiotherapy
Acetylcysteine
Cytotoxicity
RNA Interference
Heterografts
Antineoplastic Agents
Hydrogen Peroxide
Toxicity
Tumors
Cell Survival
Screening

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

Cite this

Yang, Y. J., Baek, J. Y., Goo, J., Shin, Y., Park, J. K., Jang, J. Y., ... Chang, T. S. (2016). Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin i. Antioxidants and Redox Signaling, 24(8), 453-469. https://doi.org/10.1089/ars.2014.6187

Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin i. / Yang, Yeon Ju; Baek, Jin Young; Goo, Jail; Shin, Yoonho; Park, Jong Kuk; Jang, Ji Yong; Wang, Su Bin; Jeong, Woojin; Lee, Hwa Jeong; Um, Hong Duck; Lee, Sang Kook; Choi, Yongseok; Rhee, Sue Goo; Chang, Tong Shin.

In: Antioxidants and Redox Signaling, Vol. 24, No. 8, 10.03.2016, p. 453-469.

Research output: Contribution to journalArticle

Yang, YJ, Baek, JY, Goo, J, Shin, Y, Park, JK, Jang, JY, Wang, SB, Jeong, W, Lee, HJ, Um, HD, Lee, SK, Choi, Y, Rhee, SG & Chang, TS 2016, 'Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin i', Antioxidants and Redox Signaling, vol. 24, no. 8, pp. 453-469. https://doi.org/10.1089/ars.2014.6187
Yang, Yeon Ju ; Baek, Jin Young ; Goo, Jail ; Shin, Yoonho ; Park, Jong Kuk ; Jang, Ji Yong ; Wang, Su Bin ; Jeong, Woojin ; Lee, Hwa Jeong ; Um, Hong Duck ; Lee, Sang Kook ; Choi, Yongseok ; Rhee, Sue Goo ; Chang, Tong Shin. / Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin i. In: Antioxidants and Redox Signaling. 2016 ; Vol. 24, No. 8. pp. 453-469.
@article{80f2d1252af248dfab1fa7453c09c059,
title = "Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin i",
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.",
author = "Yang, {Yeon Ju} and Baek, {Jin Young} and Jail Goo and Yoonho Shin and Park, {Jong Kuk} and Jang, {Ji Yong} and Wang, {Su Bin} and Woojin Jeong and Lee, {Hwa Jeong} and Um, {Hong Duck} and Lee, {Sang Kook} and Yongseok Choi and Rhee, {Sue Goo} and Chang, {Tong Shin}",
year = "2016",
month = "3",
day = "10",
doi = "10.1089/ars.2014.6187",
language = "English",
volume = "24",
pages = "453--469",
journal = "Antioxidants and Redox Signaling",
issn = "1523-0864",
publisher = "Mary Ann Liebert Inc.",
number = "8",

}

TY - JOUR

T1 - Effective Killing of Cancer Cells Through ROS-Mediated Mechanisms by AMRI-59 Targeting Peroxiredoxin i

AU - Yang, Yeon Ju

AU - Baek, Jin Young

AU - Goo, Jail

AU - Shin, Yoonho

AU - Park, Jong Kuk

AU - Jang, Ji Yong

AU - Wang, Su Bin

AU - Jeong, Woojin

AU - Lee, Hwa Jeong

AU - Um, Hong Duck

AU - Lee, Sang Kook

AU - Choi, Yongseok

AU - Rhee, Sue Goo

AU - Chang, Tong Shin

PY - 2016/3/10

Y1 - 2016/3/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84962589825&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84962589825&partnerID=8YFLogxK

U2 - 10.1089/ars.2014.6187

DO - 10.1089/ars.2014.6187

M3 - Article

C2 - 26528922

AN - SCOPUS:84962589825

VL - 24

SP - 453

EP - 469

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

SN - 1523-0864

IS - 8

ER -