The antitumor agent imexon activates antioxidant gene expression: Evidence for an oxidative stress response

Amanda F Baker, Terry H Landowski, Robert T Dorr, Wendy R. Tate, Jaime M C Gard, Breonna E. Tavenner, Tomislov Dragovich, Amy Coon, Garth Powis

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Purpose: The aim of this study was to identify biomarkers that may be predictive for the clinical activity of the redox-active antitumor agent imexon. Experimental Design: cDNA microarray and quantitative real-time PCR were used to identify global changes in gene expression in peripheral blood mononuclear cells (PBMC) collected from patients treated with imexon during a phase I trial. Electrophoretic mobility shift assays and Western blot analysis were done using the RPMI8226 myeloma cell line grown in vitro and PBMCs treated ex vivo to investigate the molecular mechanism responsible for these gene changes. Results: Both cDNA microarray and quantitative real-time PCR showed the up-regulation of many antioxidant genes, including thioredoxin reductase-1, glutaredoxin-2, and peroxiredoxin-3 in PBMCs collected from patients treated with imexon. Studies in PBMCs treated ex vivo and RPMI8226 myeloma cells showed that imexon increased binding to the activator protein-1 consensus sequence measured by electrophoretic mobility shift assay. Supershift analysis showed that the majority of the activator protein-1DNA binding activity was c-Jun, with minor contribution of Jun-D. Nuclear translocation of the nuclear factor (erythroid-derived 1)-like 2 transcription factor and its binding to the antioxidant response element was also increased after imexon treatment, which correlated with an increase in the message levels for nuclear factor (erythroid-derived 1)-like 2/antioxidant response element - regulated antioxidant genes. Conclusions: Together, these results show that a predominant biological effect of imexon is a change in redox state that can be detected in surrogate normal tissues as increased redox-sensitive transcription factor binding and increased antioxidant gene expression.

Original languageEnglish (US)
Pages (from-to)3388-3394
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number11
DOIs
StatePublished - Jun 1 2007

Fingerprint

Antineoplastic Agents
Oxidative Stress
Antioxidants
Gene Expression
GATA1 Transcription Factor
Antioxidant Response Elements
Oxidation-Reduction
Electrophoretic Mobility Shift Assay
Oligonucleotide Array Sequence Analysis
Peroxiredoxin III
Real-Time Polymerase Chain Reaction
Thioredoxin Reductase 1
Transcription Factors
Glutaredoxins
Genes
Transcription Factor AP-1
Consensus Sequence
Protein Binding
4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one
Blood Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The antitumor agent imexon activates antioxidant gene expression : Evidence for an oxidative stress response. / Baker, Amanda F; Landowski, Terry H; Dorr, Robert T; Tate, Wendy R.; Gard, Jaime M C; Tavenner, Breonna E.; Dragovich, Tomislov; Coon, Amy; Powis, Garth.

In: Clinical Cancer Research, Vol. 13, No. 11, 01.06.2007, p. 3388-3394.

Research output: Contribution to journalArticle

Baker, Amanda F ; Landowski, Terry H ; Dorr, Robert T ; Tate, Wendy R. ; Gard, Jaime M C ; Tavenner, Breonna E. ; Dragovich, Tomislov ; Coon, Amy ; Powis, Garth. / The antitumor agent imexon activates antioxidant gene expression : Evidence for an oxidative stress response. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 11. pp. 3388-3394.
@article{7c7da2ad64b04660b401327ce1b98bee,
title = "The antitumor agent imexon activates antioxidant gene expression: Evidence for an oxidative stress response",
abstract = "Purpose: The aim of this study was to identify biomarkers that may be predictive for the clinical activity of the redox-active antitumor agent imexon. Experimental Design: cDNA microarray and quantitative real-time PCR were used to identify global changes in gene expression in peripheral blood mononuclear cells (PBMC) collected from patients treated with imexon during a phase I trial. Electrophoretic mobility shift assays and Western blot analysis were done using the RPMI8226 myeloma cell line grown in vitro and PBMCs treated ex vivo to investigate the molecular mechanism responsible for these gene changes. Results: Both cDNA microarray and quantitative real-time PCR showed the up-regulation of many antioxidant genes, including thioredoxin reductase-1, glutaredoxin-2, and peroxiredoxin-3 in PBMCs collected from patients treated with imexon. Studies in PBMCs treated ex vivo and RPMI8226 myeloma cells showed that imexon increased binding to the activator protein-1 consensus sequence measured by electrophoretic mobility shift assay. Supershift analysis showed that the majority of the activator protein-1DNA binding activity was c-Jun, with minor contribution of Jun-D. Nuclear translocation of the nuclear factor (erythroid-derived 1)-like 2 transcription factor and its binding to the antioxidant response element was also increased after imexon treatment, which correlated with an increase in the message levels for nuclear factor (erythroid-derived 1)-like 2/antioxidant response element - regulated antioxidant genes. Conclusions: Together, these results show that a predominant biological effect of imexon is a change in redox state that can be detected in surrogate normal tissues as increased redox-sensitive transcription factor binding and increased antioxidant gene expression.",
author = "Baker, {Amanda F} and Landowski, {Terry H} and Dorr, {Robert T} and Tate, {Wendy R.} and Gard, {Jaime M C} and Tavenner, {Breonna E.} and Tomislov Dragovich and Amy Coon and Garth Powis",
year = "2007",
month = "6",
day = "1",
doi = "10.1158/1078-0432.CCR-06-0873",
language = "English (US)",
volume = "13",
pages = "3388--3394",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - The antitumor agent imexon activates antioxidant gene expression

T2 - Evidence for an oxidative stress response

AU - Baker, Amanda F

AU - Landowski, Terry H

AU - Dorr, Robert T

AU - Tate, Wendy R.

AU - Gard, Jaime M C

AU - Tavenner, Breonna E.

AU - Dragovich, Tomislov

AU - Coon, Amy

AU - Powis, Garth

PY - 2007/6/1

Y1 - 2007/6/1

N2 - Purpose: The aim of this study was to identify biomarkers that may be predictive for the clinical activity of the redox-active antitumor agent imexon. Experimental Design: cDNA microarray and quantitative real-time PCR were used to identify global changes in gene expression in peripheral blood mononuclear cells (PBMC) collected from patients treated with imexon during a phase I trial. Electrophoretic mobility shift assays and Western blot analysis were done using the RPMI8226 myeloma cell line grown in vitro and PBMCs treated ex vivo to investigate the molecular mechanism responsible for these gene changes. Results: Both cDNA microarray and quantitative real-time PCR showed the up-regulation of many antioxidant genes, including thioredoxin reductase-1, glutaredoxin-2, and peroxiredoxin-3 in PBMCs collected from patients treated with imexon. Studies in PBMCs treated ex vivo and RPMI8226 myeloma cells showed that imexon increased binding to the activator protein-1 consensus sequence measured by electrophoretic mobility shift assay. Supershift analysis showed that the majority of the activator protein-1DNA binding activity was c-Jun, with minor contribution of Jun-D. Nuclear translocation of the nuclear factor (erythroid-derived 1)-like 2 transcription factor and its binding to the antioxidant response element was also increased after imexon treatment, which correlated with an increase in the message levels for nuclear factor (erythroid-derived 1)-like 2/antioxidant response element - regulated antioxidant genes. Conclusions: Together, these results show that a predominant biological effect of imexon is a change in redox state that can be detected in surrogate normal tissues as increased redox-sensitive transcription factor binding and increased antioxidant gene expression.

AB - Purpose: The aim of this study was to identify biomarkers that may be predictive for the clinical activity of the redox-active antitumor agent imexon. Experimental Design: cDNA microarray and quantitative real-time PCR were used to identify global changes in gene expression in peripheral blood mononuclear cells (PBMC) collected from patients treated with imexon during a phase I trial. Electrophoretic mobility shift assays and Western blot analysis were done using the RPMI8226 myeloma cell line grown in vitro and PBMCs treated ex vivo to investigate the molecular mechanism responsible for these gene changes. Results: Both cDNA microarray and quantitative real-time PCR showed the up-regulation of many antioxidant genes, including thioredoxin reductase-1, glutaredoxin-2, and peroxiredoxin-3 in PBMCs collected from patients treated with imexon. Studies in PBMCs treated ex vivo and RPMI8226 myeloma cells showed that imexon increased binding to the activator protein-1 consensus sequence measured by electrophoretic mobility shift assay. Supershift analysis showed that the majority of the activator protein-1DNA binding activity was c-Jun, with minor contribution of Jun-D. Nuclear translocation of the nuclear factor (erythroid-derived 1)-like 2 transcription factor and its binding to the antioxidant response element was also increased after imexon treatment, which correlated with an increase in the message levels for nuclear factor (erythroid-derived 1)-like 2/antioxidant response element - regulated antioxidant genes. Conclusions: Together, these results show that a predominant biological effect of imexon is a change in redox state that can be detected in surrogate normal tissues as increased redox-sensitive transcription factor binding and increased antioxidant gene expression.

UR - http://www.scopus.com/inward/record.url?scp=34250613899&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34250613899&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-06-0873

DO - 10.1158/1078-0432.CCR-06-0873

M3 - Article

C2 - 17545547

AN - SCOPUS:34250613899

VL - 13

SP - 3388

EP - 3394

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 11

ER -