ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells

Katherine Aird, Jennifer L. Allensworth, Ines Batinic-Haberle, H. Kim Lyerly, Mark W. Dewhirst, Gayathri R. Devi

Research output: Contribution to journalArticle

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Abstract

Overexpression of epidermal growth factor receptors (ErbB) is frequently seen in inflammatory breast cancer (IBC). Treatment with ErbB1/2-targeting agents (lapatinib) mediates tumor apoptosis by downregulating ErbB1/2 phosphorylation and downstream survival signaling. In this study, using carboxy-H 2DCFDA, DHE, and MitoSOX Red to examine changes in hydrogen peroxide radicals, cytoplasmic and mitochondrial superoxide, respectively, we observed that GW583340 (a lapatinib-analog) increases reactive oxygen species (ROS) in two models of IBC (SUM149, SUM190) that are sensitive to ErbB1/2 blockade. This significant increase in ROS levels was similar to those generated by classical oxidative agents H 2O 2 and paraquat. In contrast, minimal to basal levels of ROS were measured in a clonal population of GW583340-resistant IBC cells (rSUM149 and rSUM190). The GW583340-resistant IBC cells displayed increased SOD1, SOD2, and glutathione expression, which correlated with decreased sensitivity to the apoptotic-inducing effects of GW583340, H 2O 2, and paraquat. The ROS increase and cell death in the GW583340-sensitive cells was reversed by simultaneous treatment with a superoxide dismutase (SOD) mimic. Additionally, overcoming the high levels of antioxidants using redox modulators induced apoptosis in the GW583340-resistant cells. Taken together, these data demonstrate a novel mechanism of lapatinib-analog-induced apoptosis and indicate that resistant cells have increased antioxidant potential, which can be overcome by treatment with SOD modulators.

Original languageEnglish (US)
Pages (from-to)109-119
Number of pages11
JournalBreast Cancer Research and Treatment
Volume132
Issue number1
DOIs
StatePublished - Feb 1 2012

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TYK2 Kinase
Inflammatory Breast Neoplasms
Oxidative Stress
Apoptosis
Reactive Oxygen Species
Paraquat
Superoxide Dismutase
Antioxidants
Superoxides
Hydrogen Peroxide
Oxidation-Reduction
Glutathione
GW 583340
Cell Death
Down-Regulation
Phosphorylation
Population

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Aird, Katherine ; Allensworth, Jennifer L. ; Batinic-Haberle, Ines ; Lyerly, H. Kim ; Dewhirst, Mark W. ; Devi, Gayathri R. / ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells. In: Breast Cancer Research and Treatment. 2012 ; Vol. 132, No. 1. pp. 109-119.
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ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells. / Aird, Katherine; Allensworth, Jennifer L.; Batinic-Haberle, Ines; Lyerly, H. Kim; Dewhirst, Mark W.; Devi, Gayathri R.

In: Breast Cancer Research and Treatment, Vol. 132, No. 1, 01.02.2012, p. 109-119.

Research output: Contribution to journalArticle

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AU - Aird, Katherine

AU - Allensworth, Jennifer L.

AU - Batinic-Haberle, Ines

AU - Lyerly, H. Kim

AU - Dewhirst, Mark W.

AU - Devi, Gayathri R.

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AB - Overexpression of epidermal growth factor receptors (ErbB) is frequently seen in inflammatory breast cancer (IBC). Treatment with ErbB1/2-targeting agents (lapatinib) mediates tumor apoptosis by downregulating ErbB1/2 phosphorylation and downstream survival signaling. In this study, using carboxy-H 2DCFDA, DHE, and MitoSOX Red to examine changes in hydrogen peroxide radicals, cytoplasmic and mitochondrial superoxide, respectively, we observed that GW583340 (a lapatinib-analog) increases reactive oxygen species (ROS) in two models of IBC (SUM149, SUM190) that are sensitive to ErbB1/2 blockade. This significant increase in ROS levels was similar to those generated by classical oxidative agents H 2O 2 and paraquat. In contrast, minimal to basal levels of ROS were measured in a clonal population of GW583340-resistant IBC cells (rSUM149 and rSUM190). The GW583340-resistant IBC cells displayed increased SOD1, SOD2, and glutathione expression, which correlated with decreased sensitivity to the apoptotic-inducing effects of GW583340, H 2O 2, and paraquat. The ROS increase and cell death in the GW583340-sensitive cells was reversed by simultaneous treatment with a superoxide dismutase (SOD) mimic. Additionally, overcoming the high levels of antioxidants using redox modulators induced apoptosis in the GW583340-resistant cells. Taken together, these data demonstrate a novel mechanism of lapatinib-analog-induced apoptosis and indicate that resistant cells have increased antioxidant potential, which can be overcome by treatment with SOD modulators.

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