title: Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner.
abstract: BACKGROUND
  Preclinical and clinical studies have shown that the proteasome inhibitor bortezomib (PS341, Velcade) is highly effective when combined with chemotherapeutic agents. The value of trastuzumab (Herceptin) in HER-2-positive (3+ score by immunohistochemistry or fluorescence in situ hybridization positive) breast cancer is also known; however, the response rate is <40% for metastatic breast cancer. These two pharmacologic agents prevent nuclear factor-kappaB (NF-kappaB) activation and induce nuclear accumulation of the cyclin-dependent kinase inhibitor p27(kip1), suggesting that combining bortezomib with trastuzumab could increase trastuzumab efficacy.
  
  
  METHODS
  Drug cytotoxicity, both individually and together, and drug effects on p27 localization and NF-kappaB activation were investigated on four breast cancer cell lines: SKBR-3 (HER-2+++), MDA-MB-453 (HER-2++), HER-2-transfected MCF-7 (HER-2+++), and MCF-7 (HER-2-).
  
  
  RESULTS
  Bortezomib induced apoptosis in HER-2-positive and HER-2-negative breast cancer cells in a dose- and time-dependent manner. Together, these drugs induced apoptosis of HER-2++/+++ cells at low concentrations, which had no effect when used alone, indicating there was a synergistic effect. Sequential treatment (trastuzumab then bortezomib) induced either necrosis or apoptosis, depending on the trastuzumab preincubation time. Susceptibility to bortezomib alone and the drug combination correlated with NF-kappaB activity and p27 localization.
  
  
  CONCLUSIONS
  The addition of bortezomib to trastuzumab increases the effect of trastuzumab in HER-2+++/++ cell lines in a synergistic way. This effect likely results from the ability of these two drugs to target the NF-kappaB and p27 pathways. The potential clinical application of this drug combination is under current evaluation by our group in a phase 1 clinical trial.
authors.affiliation: Translational Research Unit, Center for Education and Research in Food and Chemical Industry, Université libre de Bruxelles, Belgium. fatima.cardoso@bordet.be
authors.forename: Fatima
authors.initials: F
authors.lastname: Cardoso
authors.forename: Virginie
authors.initials: V
authors.lastname: Durbecq
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Laes
authors.forename: Bassam
authors.initials: B
authors.lastname: Badran
authors.forename: Laurence
authors.initials: L
authors.lastname: Lagneaux
authors.forename: Françoise
authors.initials: F
authors.lastname: Bex
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.forename: Karen
authors.initials: K
authors.lastname: Willard-Gallo
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Ross
authors.forename: Arsène
authors.initials: A
authors.lastname: Burny
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001897:Boronic Acids; D000069286:Bortezomib; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016328:NF-kappa B; D011719:Pyrazines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab