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-H2DCFDA, 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 H2O2 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, H2O2, 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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Abbreviations
- AMPK:
-
AMP activated protein kinase
- DHE:
-
Dihydroethidium
- ER:
-
Estrogen receptor
- IBC:
-
Inflammatory breast cancer
- IRES:
-
Internal ribosomal entry site
- NFκB:
-
Nuclear factor kappa B
- PR:
-
Progesterone receptor
- ROS:
-
Reactive oxygen species
- SOD:
-
Superoxide dismutase
- XIAP:
-
X-linked inhibitor of apoptosis protein
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Acknowledgments
The authors would like to thank Sharon Peplinski for her technical help with flow cytometry-based experiments and Dr. Neil Spector and Dr. Michael Morse for helpful discussions during the preparation of the manuscript. This work was supported by funding from American Cancer Society RSG-08-290-01-CCE (GRD), Department of Defense Predoctoral award, W81XWH-08-1-0363 (KMA), Viral Oncology Training Grant, 5T32-CA009111-32 (JLA) and SPORE in breast cancer grant (5P50-CA068438) at Duke Comprehensive Cancer Center.
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Aird, K.M., Allensworth, J.L., Batinic-Haberle, I. et al. ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells. Breast Cancer Res Treat 132, 109–119 (2012). https://doi.org/10.1007/s10549-011-1568-1
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DOI: https://doi.org/10.1007/s10549-011-1568-1