| ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells. | |
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MedLine Citation:
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PMID: 21559822 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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(2)DCFDA, 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(2)O(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(2)O(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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Authors:
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Katherine M Aird; Jennifer L Allensworth; Ines Batinic-Haberle; H Kim Lyerly; Mark W Dewhirst; Gayathri R Devi |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-11 |
Journal Detail:
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Title: Breast cancer research and treatment Volume: - ISSN: 1573-7217 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-11 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8111104 Medline TA: Breast Cancer Res Treat Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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