NF-kappaB inhibition through proteasome inhibition or IKKbeta blockade increases the susceptibility of melanoma cells to cytostatic treatment through distinct pathways.
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.
Amschler
Katharina
K
Department of Dermatology and Venereology, Georg August University, Göttingen, Germany.
Schön
Michael P
MP
Pletz
Nadin
N
Wallbrecht
Katrin
K
Erpenbeck
Luise
L
Schön
Margarete
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002166:Camptothecin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
C502972:7-(2-(cyclopropylmethoxy)-6-hydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido(2,3-d)(1,3)oxazin-2-one; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D001897:Boronic Acids; D016328:NF-kappa B; D010078:Oxazines; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D000069286:Bortezomib; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496562:Ikbkb protein, mouse; D046988:Proteasome Endopeptidase Complex; D002166:Camptothecin