title: NF-kappa B-mediated chemoresistance in breast cancer cells.
abstract: BACKGROUND
  Nuclear factor-kappa B (NF-kappa B) is a known survival pathway, and it may explain differential sensitivity to tumor necrosis factor-alpha (TNF-alpha) and chemotherapeutic-induced apoptosis in apoptotically sensitive (APO+) and apoptotically resistant (APO-) Michigan Cancer Foundation-7 breast cancer cells.
  
  
  METHODS
  Crystal violet viability and luciferase reporter gene assays were used to determine the inhibitory concentration of viability at 50% (IC(50)) and the inhibitory concentration of activity at 50% (EC(50)) values in APO- and APO+ cells with the selective NF-kappa B inhibitor, BAY 11-7082 (BAY). The apoptotic reporter assay was used to determine the effects of the transfection of the inhibitory kappa B-dominant negative (I kappa B-DN) construct in conjunction with TNF, paclitaxel, or doxorubicin treatments in these cells.
  
  
  RESULTS
  The concentrations at which 50% of cell viability is inhibited (IC(50)) and at which 50% of NF-kappa B activity is inhibited (EC(50)) for BAY in APO- and APO+ cells were 95.24 micromol/L and 1.53 micromol/L, respectively, and 7.62 micromol/L and 2.64 micromol/L, respectively. The IC(50) and the EC(50) values were equivalent for the APO+ cells (P =.665), but not for the APO- cells (P =.025). I kappa B-DN--transfection alone, or with TNF, doxorubicin, or paclitaxel treatments resulted in cell death of both APO- and APO+ cells as compared with vector-control; however, greater cytotoxicity was seen in the APO+ cells. Direct comparison of the APO+ cells versus the APO- cells revealed that these differences were significant (P =.05).
  
  
  CONCLUSIONS
  Pharmacologic or molecular inhibition of the NF-kappa B pathway blocked cell survival in MCF-7 APO+ cells, while only molecular inhibition induced cytotoxicity in the APO- cells. Selective manipulation of the NF-kappa B pathway in combination with standard chemotherapeutic agents may lead to an increased potency and efficacy of these agents.
authors.affiliation: Department of Surgery, Tulane/Xavier Center for Bioenvironmental Research, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: C B
authors.initials: CB
authors.lastname: Weldon
authors.forename: M E
authors.initials: ME
authors.lastname: Burow
authors.forename: K W
authors.initials: KW
authors.lastname: Rolfe
authors.forename: J L
authors.initials: JL
authors.lastname: Clayton
authors.forename: B M
authors.initials: BM
authors.lastname: Jaffe
authors.forename: B S
authors.initials: BS
authors.lastname: Beckman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D020128:Inhibitory Concentration 50; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D009570:Nitriles; D009930:Organic Chemicals; D017239:Paclitaxel / Q000494:pharmacology; D013450:Sulfones; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D009570:Nitriles; D009930:Organic Chemicals; D013450:Sulfones; D004317:Doxorubicin; D008156:Luciferases; D017239:Paclitaxel