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

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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-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

References

  1. Anderson WF, Schairer C, Chen BE, Hance KW, Levine PH (2005) Epidemiology of inflammatory breast cancer (IBC). Breast Dis 22:9–23

    PubMed  Google Scholar 

  2. Woodward WA, Cristofanilli M (2009) Inflammatory breast cancer. Semin Radiat Oncol 19:256–265

    Article  PubMed  Google Scholar 

  3. Van den Eynden GG, Van der Auwera I, Van Laere S, Colpaert CG, van Dam P, Merajver S, Kleer CG, Harris AL, Van Marck EA, Dirix LY et al (2004) Validation of a tissue microarray to study differential protein expression in inflammatory and non-inflammatory breast cancer. Breast Cancer Res Treat 85:13–22

    Article  PubMed  Google Scholar 

  4. Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL (2002) Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21:6255–6263

    Article  PubMed  CAS  Google Scholar 

  5. Xia W, Bisi J, Strum J, Liu L, Carrick K, Graham KM, Treece AL, Hardwicke MA, Dush M, Liao Q et al (2006) Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers. Cancer Res 66:1640–1647

    Article  PubMed  CAS  Google Scholar 

  6. Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ et al (2008) Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res 68:7905–7914

    Article  PubMed  CAS  Google Scholar 

  7. Polli JW, Humphreys JE, Harmon KA, Castellino S, O’Mara MJ, Olson KL, John-Williams LS, Koch KM, Serabjit-Singh CJ (2008) The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metab Dispos 36:695–701

    Article  PubMed  CAS  Google Scholar 

  8. Spector NL, Yarden Y, Smith B, Lyass L, Trusk P, Pry K, Hill JE, Xia W, Seger R, Bacus SS (2007) Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells. Proc Natl Acad Sci USA 104:10607–10612

    Google Scholar 

  9. Johnston S, Trudeau M, Kaufman B, Boussen H, Blackwell K, LoRusso P, Lombardi DP, Ben Ahmed S, Citrin DL, DeSilvio ML et al (2008) Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol 26:1066–1072

    Article  PubMed  CAS  Google Scholar 

  10. Chen FL, Xia W, Spector NL (2008) Acquired resistance to small molecule ErbB2 tyrosine kinase inhibitors. Clin Cancer Res 14:6730–6734

    Article  PubMed  CAS  Google Scholar 

  11. Aird KM, Ghanayem RB, Peplinski S, Lyerly HK, Devi GR (2010) X-linked inhibitor of apoptosis protein inhibits apoptosis in inflammatory breast cancer cells with acquired resistance to an ErbB1/2 tyrosine kinase inhibitor. Mol Cancer Ther 9:1432–1442

    Article  PubMed  CAS  Google Scholar 

  12. Xia W, Bacus S, Hegde P, Husain I, Strum J, Liu L, Paulazzo G, Lyass L, Trusk P, Hill J et al (2006) A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci USA 103:7795–7800

    Article  PubMed  CAS  Google Scholar 

  13. Martin AP, Miller A, Emad L, Rahmani M, Walker T, Mitchell C, Hagan MP, Park MA, Yacoub A, Fisher PB et al (2008) Lapatinib resistance in HCT116 cells is mediated by elevated MCL-1 expression and decreased BAK activation and not by ERBB receptor kinase mutation. Mol Pharmacol 74:807–822

    Article  PubMed  CAS  Google Scholar 

  14. Xia W, Bacus S, Husain I, Liu L, Zhao S, Liu Z, Moseley MA 3rd, Thompson JW, Chen FL, Koch KM et al (2010) Resistance to ErbB2 tyrosine kinase inhibitors in breast cancer is mediated by calcium-dependent activation of RelA. Mol Cancer Ther 9:292–299

    Article  PubMed  CAS  Google Scholar 

  15. Hardie DG (2004) The AMP-activated protein kinase pathway—new players upstream and downstream. J Cell Sci 117:5479–5487

    Article  PubMed  CAS  Google Scholar 

  16. Shell SA, Lyass L, Trusk PB, Pry KJ, Wappel RL, Bacus SS (2008) Activation of AMPK is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle 7:1769–1775

    Article  PubMed  CAS  Google Scholar 

  17. Holcik M, Lefebvre C, Yeh C, Chow T, Korneluk RG (1999) A new internal-ribosome-entry-site motif potentiates XIAP-mediated cytoprotection. Nat Cell Biol 1:190–192

    Article  PubMed  CAS  Google Scholar 

  18. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922

    Article  PubMed  CAS  Google Scholar 

  19. Agostinelli E, Seiler N (2006) Non-irradiation-derived reactive oxygen species (ROS) and cancer: therapeutic implications. Amino Acids 31:341–355

    Article  PubMed  CAS  Google Scholar 

  20. Choi SL, Kim SJ, Lee KT, Kim J, Mu J, Birnbaum MJ, Soo Kim S, Ha J (2001) The regulation of AMP-activated protein kinase by H(2)O(2). Biochem Biophys Res Commun 287:92–97

    Article  PubMed  CAS  Google Scholar 

  21. Gordon LI, Burke MA, Singh AT, Prachand S, Lieberman ED, Sun L, Naik TJ, Prasad SV, Ardehali H (2009) Blockade of the erbB2 receptor induces cardiomyocyte death through mitochondrial and reactive oxygen species-dependent pathways. J Biol Chem 284:2080–2087

    Article  PubMed  CAS  Google Scholar 

  22. Aird KM, Ding X, Baras A, Wei J, Morse MA, Clay T, Lyerly HK, Devi GR (2008) Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression. Mol Cancer Ther 7:38–47

    Article  PubMed  CAS  Google Scholar 

  23. Amantana A, London CA, Iversen PL, Devi GR (2004) X-linked inhibitor of apoptosis protein inhibition induces apoptosis and enhances chemotherapy sensitivity in human prostate cancer cells. Mol Cancer Ther 3:699–707

    PubMed  CAS  Google Scholar 

  24. Eruslanov E, Kusmartsev S (2010) Identification of ROS using oxidized DCFDA and flow-cytometry. Methods Mol Biol 594:57–72

    Article  PubMed  CAS  Google Scholar 

  25. Elorza A, Hyde B, Mikkola HK, Collins S, Shirihai OS (2008) UCP2 modulates cell proliferation through the MAPK/ERK pathway during erythropoiesis and has no effect on heme biosynthesis. J Biol Chem 283:30461–30470

    Article  PubMed  CAS  Google Scholar 

  26. Miao L, St Clair DK (2009) Regulation of superoxide dismutase genes: implications in disease. Free Radic Biol Med 47:344–356

    Article  PubMed  CAS  Google Scholar 

  27. Balendiran GK, Dabur R, Fraser D (2004) The role of glutathione in cancer. Cell Biochem Funct 22:343–352

    Article  PubMed  CAS  Google Scholar 

  28. Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W (2000) Superoxide dismutase as a target for the selective killing of cancer cells. Nature 407:390–395

    Article  PubMed  CAS  Google Scholar 

  29. Trachootham D, Alexandre J, Huang P (2009) Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat Rev Drug Discov 8:579–591

    Article  PubMed  CAS  Google Scholar 

  30. Batinic-Haberle I (2002) Manganese porphyrins and related compounds as mimics of superoxide dismutase. Methods Enzymol 349:223–233

    Article  PubMed  CAS  Google Scholar 

  31. Fernandes AS, Gaspar J, Cabral MF, Rueff J, Castro M, Batinic-Haberle I, Costa J, Oliveira NG (2010) Protective role of ortho-substituted Mn(III) N-alkylpyridylporphyrins against the oxidative injury induced by tert-butylhydroperoxide. Free Radic Res 44:430–440

    Article  PubMed  CAS  Google Scholar 

  32. Saba H, Batinic-Haberle I, Munusamy S, Mitchell T, Lichti C, Megyesi J, MacMillan-Crow LA (2007) Manganese porphyrin reduces renal injury and mitochondrial damage during ischemia/reperfusion. Free Radic Biol Med 42:1571–1578

    Article  PubMed  CAS  Google Scholar 

  33. Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT et al (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127–132

    Article  PubMed  CAS  Google Scholar 

  34. Chinnaiyan AM, Prasad U, Shankar S, Hamstra DA, Shanaiah M, Chenevert TL, Ross BD, Rehemtulla A (2000) Combined effect of tumor necrosis factor-related apoptosis-inducing ligand and ionizing radiation in breast cancer therapy. Proc Natl Acad Sci USA 97:1754–1759

    Article  PubMed  CAS  Google Scholar 

  35. Jones RG, Thompson CB (2009) Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 23:537–548

    Article  PubMed  CAS  Google Scholar 

  36. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, Clark L, Bayani N, Coppe JP, Tong F et al (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10:515–527

    Article  PubMed  CAS  Google Scholar 

  37. Contreras CM, Gurumurthy S, Haynie JM, Shirley LJ, Akbay EA, Wingo SN, Schorge JO, Broaddus RR, Wong KK, Bardeesy N et al (2008) Loss of Lkb1 provokes highly invasive endometrial adenocarcinomas. Cancer Res 68:759–766

    Article  PubMed  CAS  Google Scholar 

  38. Hardie DG (2007) AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 47:185–210

    Article  PubMed  CAS  Google Scholar 

  39. Batinic-Haberle I, Reboucas JS, Spasojevic I (2010) Superoxide dismutase mimics: chemistry, pharmacology, and therapeutic potential. Antioxid Redox Signal 13:877–918

    Google Scholar 

  40. Zhao Y, Chaiswing L, Oberley TD, Batinic-Haberle I, St Clair W, Epstein CJ, St Clair D (2005) A mechanism-based antioxidant approach for the reduction of skin carcinogenesis. Cancer Res 65:1401–1405

    Article  PubMed  CAS  Google Scholar 

  41. Batinic-Haberle I, Spasojevic I, Tse HM, Tovmasyan A, Rajic Z, St Clair DK, Vujaskovic Z, Dewhirst MW, Piganelli JD (2010) Design of Mn porphyrins for treating oxidative stress injuries and their redox-based regulation of cellular transcriptional activities. Amino Acids. doi:10.1007/s00726-010-0603-6

  42. Kong Q, Beel JA, Lillehei KO (2000) A threshold concept for cancer therapy. Med Hypotheses 55:29–35

    Article  PubMed  CAS  Google Scholar 

  43. Roninson IB, Brown JM, Bredesen DE (2008) Beyond apoptosis: cellular outcomes of cancer therapy. Informa Healthcare, New York

    Google Scholar 

  44. Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM (2004) Antioxidants and cancer therapy: a systematic review. J Clin Oncol 22:517–528

    Article  PubMed  CAS  Google Scholar 

  45. Halliwell B, Gutteridge JMC (1985) Free radicals in biology and medicine. Clarendon Press, Oxford University Press, Oxford, New York

  46. Li S, Yan T, Yang JQ, Oberley TD, Oberley LW (2000) The role of cellular glutathione peroxidase redox regulation in the suppression of tumor cell growth by manganese superoxide dismutase. Cancer Res 60:3927–3939

    PubMed  CAS  Google Scholar 

  47. Landriscina M, Maddalena F, Laudiero G, Esposito F (2009) Adaptation to oxidative stress, chemoresistance, and cell survival. Antioxid Redox Signal 11:2701–2716

    Article  PubMed  CAS  Google Scholar 

  48. Khan G, Merajver S (2009) Copper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm. Expert Opin Investig Drugs 18:541–548

    Article  PubMed  CAS  Google Scholar 

  49. Heikkila RE, Cabbat FS, Cohen G (1976) In vivo inhibition of superoxide dismutase in mice by diethyldithiocarbamate. J Biol Chem 251:2182–2185

    PubMed  CAS  Google Scholar 

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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.

Conflicts of interest

All authors state that there is no conflict of interest.

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Author notes

  1. Katherine M. Aird

    Present address: Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

Authors and Affiliations

  1. Department of Surgery, Duke University Medical Center, Durham, Box 2606, NC, 27710, USA

    H. Kim Lyerly & Gayathri R. Devi

  2. Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC, 27710, USA

    H. Kim Lyerly, Mark W. Dewhirst & Gayathri R. Devi

  3. Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA

    Katherine M. Aird, Jennifer L. Allensworth, H. Kim Lyerly, Mark W. Dewhirst & Gayathri R. Devi

  4. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27710, USA

    Ines Batinic-Haberle & Mark W. Dewhirst

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  1. Katherine M. Aird
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  2. Jennifer L. Allensworth
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  3. Ines Batinic-Haberle
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Correspondence to Gayathri R. Devi.

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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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