Breast Cancer Research and Treatment

, Volume 111, Issue 3, pp 419–427

NF-κB pathway inhibitors preferentially inhibit breast cancer stem-like cells

  • Jiangbing Zhou
  • Hao Zhang
  • Peihua Gu
  • Jining Bai
  • Joseph B. Margolick
  • Ying Zhang
Preclinical Study

Abstract

Accumulating evidence indicates that breast cancer is caused by cancer stem cells and cure of breast cancer requires eradication of breast cancer stem cells. Previous studies with leukemia stem cells have shown that NF-κB pathway is important for leukemia stem cell survival. In this study, by using MCF7 sphere cells as model of breast cancer stem-like cells, we evaluated the effect of NF-κB pathway specific inhibitors on human breast cancer MCF7 sphere cells. Three inhibitors including parthenolide (PTL), pyrrolidinedithiocarbamate (PDTC) and its analog diethyldithiocarbamate (DETC) were found to preferentially inhibit MCF7 sphere cell proliferation. These compounds also showed preferential inhibition in term of proliferation and colony formation on MCF7 side population (SP) cells, a small fraction of MCF7 cells known to enrich in breast cancer stem-like cells. The preferential inhibition effect of these compounds was due to inhibition of the NF-κB activity in both MCF7 sphere and MCF7 cells, with higher inhibition effect on MCF7 sphere cells than on MCF7 cells. PDTC was further evaluated in vivo and showed significant tumor growth inhibition alone but had better tumor growth inhibition in combination with paclitaxel in the mouse xenograft model than either PDTC or paclitaxel alone. This study suggests that breast cancer stem-like cells could be selectively inhibited by targeting signaling pathways important for breast cancer stem-like cells.

Keywords

Breast cancer stem-like cells Side population cells NF-κB Sphere cells Xenograft 

Abbreviations

PTL

Parthenolide

PDTC

Pyrrolidinedithiocarbamate

DETC

Diethyldithiocarbamate

SP

Side population

ABC

ATP-binding cassette

References

  1. 1.
    Howe HL, Wingo PA, Thun MJ, Ries LA, Rosenberg HM, Feigal EG, Edwards BK (2001) Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. J Natl Cancer Inst 93:824–842PubMedCrossRefGoogle Scholar
  2. 2.
    Peto R, Boreham J, Clarke M, Davies C, Beral V (2000) UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years. Lancet 355:1822PubMedCrossRefGoogle Scholar
  3. 3.
    EBCT (1998) Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 352:930–942CrossRefGoogle Scholar
  4. 4.
    EBCT (1998) Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 351:1451–1467CrossRefGoogle Scholar
  5. 5.
    Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988PubMedCrossRefGoogle Scholar
  6. 6.
    Al-Hajj M, Becker MW, Wicha M, Weissman I, Clarke MF (2004) Therapeutic implications of cancer stem cells. Curr Opin Genet Dev 14:43–47PubMedCrossRefGoogle Scholar
  7. 7.
    Jones RJ, Matsui WH, Smith BD (2004) Cancer stem cells: are we missing the target? J Natl Cancer Inst 96:583–585PubMedGoogle Scholar
  8. 8.
    Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111PubMedCrossRefGoogle Scholar
  9. 9.
    Donnenberg VS, Donnenberg AD (2005) Multiple drug resistance in cancer revisited: the cancer stem cell hypothesis. J Clin Pharmacol 45:872–877PubMedCrossRefGoogle Scholar
  10. 10.
    Guzman ML, Jordan CT (2004) Considerations for targeting malignant stem cells in leukemia. Cancer Control 11:97–104PubMedGoogle Scholar
  11. 11.
    Costello RT, Mallet F, Gaugler B, Sainty D, Arnoulet C, Gastaut JA, Olive D (2000) Human acute myeloid leukemia CD34+/CD38− progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res 60:4403–4411PubMedGoogle Scholar
  12. 12.
    Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL (2002) Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99:319–325PubMedCrossRefGoogle Scholar
  13. 13.
    Angstreich GR, Matsui W, Huff CA, Vala MS, Barber J, Hawkins AL, Griffin CA, Smith BD, Jones RJ (2005) Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors. Br J Haematol 130:373–381PubMedCrossRefGoogle Scholar
  14. 14.
    Behbod F, Rosen JM (2005) Will cancer stem cells provide new therapeutic targets? Carcinogenesis 26:703–711PubMedCrossRefGoogle Scholar
  15. 15.
    Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5:275–284PubMedCrossRefGoogle Scholar
  16. 16.
    Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti MA, Daidone MG (2005) Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 65:5506–5511PubMedCrossRefGoogle Scholar
  17. 17.
    Kondo T, Setoguchi T, Taga T (2004) Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA 101:781–786PubMedCrossRefGoogle Scholar
  18. 18.
    Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG (2005) Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2− cancer cells are similarly tumorigenic. Cancer Res 65:6207–6219PubMedCrossRefGoogle Scholar
  19. 19.
    Goodell MA, Rosenzweig M, Kim H, Marks DF, DeMaria M, Paradis G, Grupp SA, Sieff CA, Mulligan RC, Johnson RP (1997) Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 3:1337–1345PubMedCrossRefGoogle Scholar
  20. 20.
    Hirschmann-Jax C, Foster AE, Wulf GG, Goodell MA, Brenner MK (2005) A distinct “side population” of cells in human tumor cells: implications for tumor biology and therapy. Cell Cycle 4:203–205PubMedGoogle Scholar
  21. 21.
    Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7:1028–1034PubMedCrossRefGoogle Scholar
  22. 22.
    Jonker JW, Freeman J, Bolscher E, Musters S, Alvi AJ, Titley I, Schinkel AH, Dale TC (2005) Contribution of the ABC-transporters Bcrp1 and Mdr1a/1b to the side population phenotype in mammary gland and bone marrow of mice. Stem Cells 23:1059–1065PubMedCrossRefGoogle Scholar
  23. 23.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737PubMedCrossRefGoogle Scholar
  24. 24.
    Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648PubMedCrossRefGoogle Scholar
  25. 25.
    Guzman ML, Neering SJ, Upchurch D, Grimes B, Howard DS, Rizzieri DA, Luger SM, Jordan CT (2001) Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98:2301–2307PubMedCrossRefGoogle Scholar
  26. 26.
    Guzman ML, Rossi RM, Karnischky L, Li X, Peterson DR, Howard DS, Jordan CT, Liesveld JL, Phillips GL, Swiderski CF, Grimes BA, Szilvassy SJ, Neering SJ, Upchurch D, Grimes B, Rizzieri DA, Luger SM, Lemischka IR, Pettigrew AL, Meyerrose T, Rossi R, Phillips GL (2005) The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood 16:708–712Google Scholar
  27. 27.
    Malaguarnera L, Pilastro MR, DiMarco R, Scifo C, Renis M, Mazzarino MC, Messina A (2003) Cell death in human acute myelogenous leukemic cells induced by pyrrolidinedithiocarbamate. Apoptosis 8:539–545PubMedCrossRefGoogle Scholar
  28. 28.
    Dontu G, Abdallah WM, Foley JM, Jackson KW, Clarke MF, Kawamura MJ, Wicha MS (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17:1253–1270PubMedCrossRefGoogle Scholar
  29. 29.
    Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC (1996) Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183:1797–1806PubMedCrossRefGoogle Scholar
  30. 30.
    Kasukabe T, Okabe-Kado J, Kato N, Sassa T, Honma Y (2005) Effects of combined treatment with rapamycin and cotylenin A, a novel differentiation-inducing agent, on human breast carcinoma MCF-7 cells and xenografts. Breast Cancer Res 7:R1097–R1110PubMedCrossRefGoogle Scholar
  31. 31.
    Hardman WE, Moyer MP, Cameron IL (1999) Fish oil supplementation enhanced CPT-11 (irinotecan) efficacy against MCF7 breast carcinoma xenografts and ameliorated intestinal side-effects. Br J Cancer 81:440–448PubMedCrossRefGoogle Scholar
  32. 32.
    Singh S, Aggarwal BB (1995) Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. J Biol Chem 270:24995–25000PubMedCrossRefGoogle Scholar
  33. 33.
    Schreck R, Meier B, Mannel DN, Droge W, Baeuerle PA (1992) Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med 175:1181–1194PubMedCrossRefGoogle Scholar
  34. 34.
    Hill WD, Hess DC, Carroll JE, Wakade CG, Howard EF, Chen Q, Cheng C, Martin-Studdard A, Waller JL, Beswick RA (2001) The NF-kappaB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia. Brain Res Bull 55:375–386PubMedCrossRefGoogle Scholar
  35. 35.
    Musonda CA, Chipman JK (1998) Quercetin inhibits hydrogen peroxide (H2O2)-induced NF-kappaB DNA binding activity and DNA damage in HepG2 cells. Carcinogenesis 19:1583–1589PubMedCrossRefGoogle Scholar
  36. 36.
    WeberCK, Liptay S, Wirth T, Adler G, Schmid RM (2000) Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology 119:1209–1218CrossRefGoogle Scholar
  37. 37.
    Yamamoto Y, Yin MJ, Lin KM, Gaynor RB (1999) Sulindac inhibits activation of the NF-kappaB pathway. J Biol Chem 274:27307–27314PubMedCrossRefGoogle Scholar
  38. 38.
    Palayoor ST, Youmell MY, Calderwood SK, Coleman CN, Price BD, Rosenzweig KE, Youmell MB (1999) Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen radiosensitization of human tumor cells by the phosphatidylinositol3-kinase inhibitors wortmannin and LY294002 correlates with inhibition of DNA-dependent protein kinase and prolonged G2-M delay. Oncogene 18:7389–7394PubMedCrossRefGoogle Scholar
  39. 39.
    Hehner SP, Heinrich M, Bork PM, Vogt M, Ratter F, Lehmann V, Schulze-Osthoff K, Droge W, Schmitz ML (1998) Sesquiterpene lactones specifically inhibit activation of NF-kappa B by preventing the degradation of I kappa B-alpha and I kappa B-beta. J Biol Chem 273:1288–1297PubMedCrossRefGoogle Scholar
  40. 40.
    Meriin AB, Gabai VL, Yaglom J, Shifrin VI, Sherman MY (1998) Proteasome inhibitors activate stress kinases and induce Hsp72. Diverse effects on apoptosis. J Biol Chem 273:6373–6379PubMedCrossRefGoogle Scholar
  41. 41.
    Meyer S, Kohler NG, Joly A (1997) Cyclosporine A is an uncompetitive inhibitor of proteasome activity and prevents NF-kappaB activation. FEBS Lett 413:354–358PubMedCrossRefGoogle Scholar
  42. 42.
    Natarajan K, Manna SK, Chaturvedi MM, Aggarwal BB (1998) Protein tyrosine kinase inhibitors block tumor necrosis factor-induced activation of nuclear factor-kappaB, degradation of IkappaBalpha, nuclear translocation of p65, and subsequent gene expression. Arch Biochem Biophys 352:59–70PubMedCrossRefGoogle Scholar
  43. 43.
    Phillips TM, McBride WH, Pajonk F (2006) The response of CD24(−/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98:1777–1785PubMedCrossRefGoogle Scholar
  44. 44.
    Renard P, Ernest I, Houbion A, Art M, Le Calvez H, Raes M, Remacle J (2001) Development of a sensitive multi-well colorimetric assay for active NFkappaB. Nucleic Acids Res 29:E21PubMedCrossRefGoogle Scholar
  45. 45.
    Weissman I (2005) Stem cell research: paths to cancer therapies and regenerative medicine. Jama 294:1359–1366PubMedCrossRefGoogle Scholar
  46. 46.
    Bonnet D (2005) Cancer stem cells: AMLs show the way. Biochem Soc Trans 33:1531–1533PubMedCrossRefGoogle Scholar
  47. 47.
    Jordan CT (2004) Cancer stem cell biology: from leukemia to solid tumors. Curr Opin Cell Biol 16:708–712PubMedCrossRefGoogle Scholar
  48. 48.
    Jordan CT, Guzman ML, Noble M (2006) Cancer stem cells. N Engl J Med 355:1253–1261PubMedCrossRefGoogle Scholar
  49. 49.
    Polyak K, Hahn WC (2006) Roots and stems: stem cells in cancer. Nat Med 12:296–300PubMedCrossRefGoogle Scholar
  50. 50.
    Zhang M, Rosen JM (2006) Stem cells in the etiology and treatment of cancer. Curr Opin Genet Dev 16:60–64PubMedCrossRefGoogle Scholar
  51. 51.
    Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M (2003) Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 102:972–980PubMedCrossRefGoogle Scholar
  52. 52.
    Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, Morrison SJ (2006) Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441:475–482PubMedCrossRefGoogle Scholar
  53. 53.
    Guzman ML, Jordan CT (2005) Feverfew: weeding out the root of leukaemia. Expert Opin Biol Ther 5:1147–1152PubMedCrossRefGoogle Scholar
  54. 54.
    Hehner SP, Hofmann TG, Droge W, Schmitz ML (1999) The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex. J Immunol 163:5617–5623PubMedGoogle Scholar
  55. 55.
    Kwok BH, Koh B, Ndubuisi MI, Elofsson M, Crews CM (2001) The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. Chem Biol 8:759–766PubMedCrossRefGoogle Scholar
  56. 56.
    Garcia-Pineres AJ, Castro V, Mora G, Schmidt TJ, Strunck E, Pahl HL, Merfort I (2001) Cysteine 38 in p65/NF-kappaB plays a crucial role in DNA binding inhibition by sesquiterpene lactones. J Biol Chem 276:39713–39720PubMedCrossRefGoogle Scholar
  57. 57.
    MacKenzie CJ, Paul A, Wilson S, de Martin R, Baker AH, Plevin R (2003) Enhancement of lipopolysaccharide-stimulated JNK activity in rat aortic smooth muscle cells by pharmacological and adenovirus-mediated inhibition of inhibitory kappa B kinase signalling. Br J Pharmacol 139:1041–1049PubMedCrossRefGoogle Scholar
  58. 58.
    Peng Y, Power MR, Li B, Lin TJ (2005) Inhibition of IKK down-regulates antigen + IgE-induced TNF production by mast cells: a role for the IKK-IkappaB-NF-kappaB pathway in IgE-dependent mast cell activation. J Leukoc Biol 77:975–983PubMedCrossRefGoogle Scholar
  59. 59.
    Sweeney CJ, Mehrotra S, Sadaria MR, Kumar S, Shortle NH, Roman Y, Sheridan C, Campbell RA, Murry DJ, Badve S, Nakshatri H (2005) The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer. Mol Cancer Ther 4:1004–1012PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2007

Authors and Affiliations

  • Jiangbing Zhou
    • 1
  • Hao Zhang
    • 1
  • Peihua Gu
    • 1
  • Jining Bai
    • 1
  • Joseph B. Margolick
    • 1
  • Ying Zhang
    • 1
  1. 1.Department of Molecular Microbiology and Immunology, Bloomberg School of Public HealthJohns Hopkins UniversityBaltimoreUSA

Personalised recommendations