NF-κB pathway inhibitors preferentially inhibit breast cancer stem-like cells
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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.
KeywordsBreast cancer stem-like cells Side population cells NF-κB Sphere cells Xenograft
Support from NIH grant AI44063, Ho Ching Yang Fellowship of Johns Hopkins Bloomberg School of Public Health, and the Johns Hopkins Center for AIDS Research, is gratefully acknowledged.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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