NF-j B pathway inhibitors preferentially inhibit breast cancer stem-like cells

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-jB 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-jB 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-jB 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.

[1]  Frank Pajonk,et al.  The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. , 2006, Journal of the National Cancer Institute.

[2]  M. Noble,et al.  Cancer stem cells. , 2006, The New England journal of medicine.

[3]  S. Morrison,et al.  Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells , 2006, Nature.

[4]  W. Hahn,et al.  Roots and stems: stem cells in cancer , 2006, Nature Medicine.

[5]  J. Rosen,et al.  Stem cells in the etiology and treatment of cancer. , 2006, Current opinion in genetics & development.

[6]  Y. Honma,et al.  Effects of combined treatment with rapamycin and cotylenin A, a novel differentiation-inducing agent, on human breast carcinoma MCF-7 cells and xenografts , 2005, Breast Cancer Research.

[7]  I. Weissman,et al.  Stem cell research: paths to cancer therapies and regenerative medicine. , 2005, JAMA.

[8]  C. Jordan,et al.  Feverfew: weeding out the root of leukaemia , 2005, Expert opinion on biological therapy.

[9]  T. Dale,et al.  Contribution of the ABC Transporters Bcrp1 and Mdr1a/1b to the Side Population Phenotype in Mammary Gland and Bone Marrow of Mice , 2005, Stem cells.

[10]  A. Donnenberg,et al.  Multiple Drug Resistance in Cancer Revisited: The Cancer Stem Cell Hypothesis , 2005, Journal of clinical pharmacology.

[11]  C. Huff,et al.  Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors , 2005, British journal of haematology.

[12]  R. Schneider-Broussard,et al.  Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. , 2005, Cancer research.

[13]  Danila Coradini,et al.  Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. , 2005, Cancer research.

[14]  Yongde Peng,et al.  Inhibition of IKK down‐regulates antigen + IgE‐induced TNF production by mast cells: a role for the IKK‐IκB‐NF‐κB pathway in IgE‐dependent mast cell activation , 2005 .

[15]  Derick R. Peterson,et al.  The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. , 2005, Blood.

[16]  S. Badve,et al.  The sesquiterpene lactone parthenolide in combination with docetaxel reduces metastasis and improves survival in a xenograft model of breast cancer , 2005, Molecular Cancer Therapeutics.

[17]  Michael Dean,et al.  Tumour stem cells and drug resistance , 2005, Nature Reviews Cancer.

[18]  Fariba Behbod,et al.  Will cancer stem cells provide new therapeutic targets? , 2005, Carcinogenesis.

[19]  M. Goodell,et al.  A Distinct “Side Population” of Cells in Human Tumor Cells: Implications for Tumor Biology and Therapy , 2005, Cell cycle.

[20]  C. Jordan.  Cancer stem cell biology: from leukemia to solid tumors. , 2004, Current opinion in cell biology.

[21]  Richard J. Jones,et al.  Cancer stem cells: are we missing the target? , 2004, Journal of the National Cancer Institute.

[22]  C. Jordan,et al.  Considerations for targeting malignant stem cells in leukemia. , 2004, Cancer control : journal of the Moffitt Cancer Center.

[23]  I. Weissman,et al.  Therapeutic implications of cancer stem cells. , 2004, Current opinion in genetics & development.

[24]  T. Kondo,et al.  Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Mazzarino,et al.  Cell death in human acute myelogenous leukemic cells induced by pyrrolidinedithiocarbamate , 2003, Apoptosis.

[26]  M. Carroll,et al.  Survival of acute myeloid leukemia cells requires PI3 kinase activation. , 2003, Blood.

[27]  R. Plevin,et al.  Enhancement of lipopolysaccharide‐stimulated JNK activity in rat aortic smooth muscle cells by pharmacological and adenovirus‐mediated inhibition of inhibitory kappa B kinase signalling , 2003, British journal of pharmacology.

[28]  G. Dontu,et al.  In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. , 2003, Genes & development.

[29]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  H. Pahl,et al.  Cysteine 38 in p65/NF-κB Plays a Crucial Role in DNA Binding Inhibition by Sesquiterpene Lactones* , 2001, The Journal of Biological Chemistry.

[31]  D. Howard,et al.  Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. , 2001, Blood.

[32]  H. Nakauchi,et al.  The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype , 2001, Nature Medicine.

[33]  H M Rosenberg,et al.  Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends. , 2001, Journal of the National Cancer Institute.

[34]  D. Hess,et al.  The NF-κB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia , 2001, Brain Research Bulletin.

[35]  D. Olive,et al.  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. , 2000, Cancer research.

[36]  Mike Clarke,et al.  UK and USA breast cancer deaths down 25% in year 2000 at ages 20–69 years , 2000, The Lancet.

[37]  I. Cameron,et al.  © 1999 Cancer Research Campaign Article no. bjoc.1999.0713 Fish oil supplementation enhanced CPT-11 (irinotecan) , 2022 .

[38]  C. A. Musonda,et al.  Quercetin inhibits hydrogen peroxide (H2O2)-induced NF-kappaB DNA binding activity and DNA damage in HepG2 cells. , 1998, Carcinogenesis.

[39]  M. Sherman,et al.  Proteasome Inhibitors Activate Stress Kinases and Induce Hsp72 , 1998, The Journal of Biological Chemistry.

[40]  R. Johnson,et al.  Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species , 1997, Nature Medicine.

[41]  A. Joly,et al.  Cyclosporine A is an uncompetitive inhibitor of proteasome activity and prevents NF‐κB activation , 1997, FEBS letters.

[42]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[43]  A. S. Conner,et al.  Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo , 1996, The Journal of experimental medicine.

[44]  M. Caligiuri,et al.  A cell initiating human acute myeloid leukaemia after transplantation into SCID mice , 1994, Nature.

[45]  D. Männel,et al.  Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells , 1992, The Journal of experimental medicine.

[46]  D. Bonnet.  Cancer stem cells: AMLs show the way. , 2005, Biochemical Society transactions.

[47]  Zang Ai-hua,et al.  Stem Cells,Cancer and Cancer Stem Cells , 2005 .

[48]  T. Holyoake,et al.  Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. , 2002, Blood.

[49]  M Elofsson,et al.  The anti-inflammatory natural product parthenolide from the medicinal herb Feverfew directly binds to and inhibits IkappaB kinase. , 2001, Chemistry & biology.

[50]  J. Remacle,et al.  Development of a sensitive multi-well colorimetric assay for active NFkappaB. , 2001, Nucleic acids research.

[51]  R. Schmid,et al.  Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. , 2000, Gastroenterology.

[52]  C. N. Coleman,et al.  Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen. , 1999, Oncogene.

[53]  T. Hofmann,et al.  The antiinflammatory sesquiterpene lactone parthenolide inhibits NF-kappa B by targeting the I kappa B kinase complex. , 1999, Journal of immunology.

[54]  R. Gaynor,et al.  Sulindac inhibits activation of the NF-kappaB pathway. , 1999, The Journal of biological chemistry.

[55]  D. Tripathy,et al.  Tamoxifen for early breast cancer: An overview of the randomised trials , 1999 .

[56]  K. Schulze-Osthoff,et al.  Sesquiterpene lactones specifically inhibit activation of NF-kappa B by preventing the degradation of I kappa B-alpha and I kappa B-beta. , 1998, The Journal of biological chemistry.

[57]  S. Manna,et al.  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. , 1998, Archives of biochemistry and biophysics.

[58]  B. Aggarwal,et al.  Activation of transcription factor NF-kappa B is suppressed by curcumin (diferuloylmethane) [corrected]. , 1995, The Journal of biological chemistry.