PloS one, 2013-02, Vol.8 (2), p.e56134
2013
Details
- Autor(en) / Beteiligte
- Titel
- Activity of the heat shock protein 90 inhibitor ganetespib in melanoma
- Ist Teil von
- PloS one, 2013-02, Vol.8 (2), p.e56134
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- Heat shock protein 90 (HSP90) is involved in the regulation of diverse biological processes such as cell signaling, proliferation and survival, and has been recently recognized as a potential target for cancer therapy. Ganetespib is a potent ATP competitive inhibitor of HSP90. Ganetespib downregulated the expression of multiple signal transducing molecules including EGFR, IGF-1R, c-Met, Akt, B-RAF and C-RAF, resulting in pronounced decrease in phosphorylation of Akt and Erk1/2 in a panel of five cutaneous melanoma cell lines including those harboring B-RAF and N-RAS mutations. Ganetespib exhibited potent antiproliferative activity on all five of these cell lines, with IC50 values between 37.5 and 84 nM. Importantly, Ganetespib is active on B-RAF mutated melanoma cells that have acquired resistance to B-RAF inhibition. Ganetespib induced apoptosis and cell cycle arrest at G1 and/or G2/M phase. Ganetespib induced cell cycle arrest was accompanied by altered expression of cyclin-dependent kinase inhibitor (CDKI) p21(Cip1) and p27(Kip1), cyclins B1, D1 and E, and/or cyclin-dependent kinases 1, 2 and 4. HSP90 is functionally important for melanoma cells and HSP90 inhibitors such as ganetespib could potentially be effective therapeutics for melanoma with various genetic mutations and acquired resistance to B-RAF inhibition.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0056134Titel-ID: cdi_plos_journals_1331591442
- Format
- –
- Schlagworte
- AKT protein, Apoptosis, Apoptosis - drug effects, B cells, Biological activity, Biology, Biotechnology, Cancer, Cancer therapies, Cancer treatment, Care and treatment, Cell cycle, Cell Cycle Checkpoints - drug effects, Cell Cycle Proteins - metabolism, Cell Line, Tumor, Cell Proliferation - drug effects, Cell survival, Cell Survival - drug effects, Cyclin-dependent kinase inhibitor p21, Cyclin-dependent kinase inhibitor p27, Cyclin-dependent kinases, Cyclins, Down-Regulation - drug effects, Enzyme inhibitors, Epidermal growth factor receptors, Extracellular signal-regulated kinase, Extracellular Signal-Regulated MAP Kinases - metabolism, Gene mutation, Gene mutations, GTP Phosphohydrolases - genetics, GTP Phosphohydrolases - metabolism, Health aspects, Heat shock proteins, HSP90 Heat-Shock Proteins - antagonists & inhibitors, HSP90 Heat-Shock Proteins - metabolism, Hsp90 protein, Humans, Immunoblotting, Inhibition, Inhibitors, Inhibitory Concentration 50, Insulin-like growth factors, Kinases, Lymphocytes B, Medicine, Melanoma, Melanoma - genetics, Melanoma - metabolism, Melanoma - pathology, Membrane Proteins - genetics, Membrane Proteins - metabolism, Metastasis, Mutation, Phosphorylation, Phosphorylation - drug effects, Phosphotransferases, Proto-Oncogene Proteins B-raf - genetics, Proto-Oncogene Proteins B-raf - metabolism, Proto-Oncogene Proteins c-akt, Raf protein, Receptor, Epidermal Growth Factor - metabolism, Receptor, IGF Type 1 - metabolism, Regulation, Response rates, Signaling, Skin cancer, Skin Neoplasms - genetics, Skin Neoplasms - metabolism, Skin Neoplasms - pathology, Target recognition, Triazoles - pharmacology, Women