NF-κB Inhibition through Proteasome Inhibition or IKKβ Blockade Increases the Susceptibility of Melanoma Cells to Cytostatic Treatment through Distinct Pathways
| Autor: | Michael P. Schön, Luise Erpenbeck, Katharina Amschler, Margarete Schön, Katrin Wallbrecht, Nadin Pletz |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Proteasome Endopeptidase Complex
Lung Neoplasms Skin Neoplasms Pyridines Antineoplastic Agents Dermatology IκB kinase Biology Biochemistry Bortezomib Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Line Tumor Oxazines medicine Animals Humans Melanoma Protein Kinase Inhibitors Molecular Biology 030304 developmental biology 0303 health sciences Kinase Cell growth NF-kappa B Drug Synergism Cell Biology Antineoplastic Agents Phytogenic Boronic Acids I-kappa B Kinase 3. Good health Gene Expression Regulation Neoplastic Drug Resistance Neoplasm Apoptosis Pyrazines 030220 oncology & carcinogenesis Cancer research Proteasome inhibitor Camptothecin Proteasome Inhibitors medicine.drug |
| Zdroj: | Journal of Investigative Dermatology. (4):1073-1086 |
| ISSN: | 0022-202X |
| DOI: | 10.1038/jid.2009.365 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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