Brummer, Christina and Faerber, Stephanie and Bruss, Christina and Blank, Christian and Lacroix, Ruben and Haferkamp, Sebastian and Herr, Wolfgang and Kreutz, Marina and Renner, Kathrin (2019) Metabolic targeting synergizes with MAPK inhibition and delays drug resistance in melanoma. CANCER LETTERS, 442. pp. 453-463. ISSN 0304-3835, 1872-7980
Full text not available from this repository. (Request a copy)Abstract
Tumors, including melanomas, frequently show an accelerated glucose metabolism. Mutations in the v-Raf murine sarcoma viral oncogene homolog B (BRAF), detected in about 50% of all melanomas, result in further enhancement of glycolysis. Therefore anti-metabolic substances might enhance the impact of RAF inhibitors. We have identified the two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and lumiracoxib being able to restrict energy metabolism in human melanoma cells by targeting lactate release and oxidative phosphorylation (OXPHOS). In combination with the RAF inhibitor vemurafenib strong synergism was observed: Diclofenac as well as lumiracoxib increased the anti-glycolytic impact of vemurafenib and prevented RAF-inhibitor induced metabolic reprogramming towards OXPHOS. Consequently, both NSAIDs sensitized melanoma cells to vemurafenib triggered proliferation arrest and enhanced the anti-tumor effect of RAF inhibitors from cytostatic to cytotoxic. Furthermore the addition of NSAIDs delayed the onset of RAF inhibitor resistance, most likely by counteracting the upregulation of MITF. Our data suggest that selected NSAIDs could be a promising combination partner for MAPK pathway inhibitors for the treatment of BRAF(V600E) mutated melanomas.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MITOCHONDRIAL OXIDATIVE-METABOLISM; BRAF-MUTANT MELANOMA; CONFERS RESISTANCE; DICLOFENAC SODIUM; CELLS; MITF; CANCER; PHARMACOKINETICS; COMBINATION; OUTCOMES; BRAF; Vemurafenib; Glycolysis; MITF; Diclofenac; NSAID |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 20 Apr 2020 07:48 |
| Last Modified: | 20 Apr 2020 07:48 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27677 |
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