NF-kappaB inhibition through proteasome inhibition or IKKbeta blockade increases the susceptibility of melanoma cells to cytostatic treatment through distinct pathways

J Invest Dermatol. 2010 Apr;130(4):1073-86. doi: 10.1038/jid.2009.365. Epub 2009 Nov 26.


Metastasized melanoma is almost universally resistant to chemotherapy. Given that constitutive or drug-induced upregulation of NF-kappaB activity is associated with this chemoresistance, NF-kappaB inhibition may increase the susceptibility to antitumoral therapy. On the cellular level, two principles of NF-kappaB inhibition, proteasome inhibition by bortezomib and IkappaB kinase-beta (IKKbeta) inhibition by the kinase inhibitor of NF-kappaB-1 (KINK-1), significantly increased the antitumoral efficacy of camptothecin. When combined with camptothecin, either of the two NF-kappaB-inhibiting principles synergistically influenced progression-related in vitro functions, including cell growth, apoptosis, and invasion through an artificial basement membrane. In addition, when C57BL/6 mice were intravenously injected with B16F10 melanoma cells, the combination of cytostatic treatment with either of the NF-kappaB-inhibiting compounds revealed significantly reduced pulmonary metastasis compared to either treatment alone. However, on the molecular level, nuclear translocation of p65, cell cycle analysis, and expression of NF-kappaB-dependent gene products disclosed distinctly different molecular mechanisms, resulting in the same functional effect. That proteasome inhibition and IKKbeta inhibition affect distinct molecular pathways downstream of NF-kappaB, both leading to increased chemosensitivity, is previously unreported. Thus, it is conceivable that switching the two principles of NF-kappaB inhibition, once resistance to one of the agents occurs, will improve future treatment regimens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Camptothecin / pharmacology*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / physiology
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Melanoma / secondary
  • Mice
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Oxazines / pharmacology
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazines / pharmacology*
  • Pyridines / pharmacology
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology


  • 7-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido(2,3-d)(1,3)oxazin-2-one
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Boronic Acids
  • NF-kappa B
  • Oxazines
  • Proteasome Inhibitors
  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyridines
  • Bortezomib
  • I-kappa B Kinase
  • IKBKB protein, human
  • Ikbkb protein, mouse
  • Proteasome Endopeptidase Complex
  • Camptothecin