| Publications [#210128] of Mark W. Dewhirst
Papers Published
- KM Aird, JL Allensworth, I Batinic-Haberle, HK Lyerly, MW Dewhirst, GR Devi, ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells.,
Breast cancer research and treatment, vol. 132 no. 1
(February, 2012),
pp. 109-19, ISSN 1573-7217 [doi]
(last updated on 2012/10/26)
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(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.
Keywords: Antioxidants • Apoptosis* • Cell Line, Tumor • Cell Survival • Drug Resistance, Neoplasm • Female • Glutathione • Humans • Inflammatory Breast Neoplasms • Membrane Potential, Mitochondrial • Oxidative Stress* • Quinazolines • Reactive Oxygen Species • Receptor, Epidermal Growth Factor • Receptor, erbB-2 • Sulfones • Superoxide Dismutase • antagonists & inhibitors* • drug effects • metabolism • pharmacology • pharmacology*
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