Abstract |
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.
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Authors | Xinqi Wu, Melina E Marmarelis, F Stephen Hodi |
Journal | PloS one
(PLoS One)
Vol. 8
Issue 2
Pg. e56134
( 2013)
ISSN: 1932-6203 [Electronic] United States |
PMID | 23418523
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cell Cycle Proteins
- HSP90 Heat-Shock Proteins
- Membrane Proteins
- STA 9090
- Triazoles
- ErbB Receptors
- Receptor, IGF Type 1
- BRAF protein, human
- Proto-Oncogene Proteins B-raf
- Proto-Oncogene Proteins c-akt
- Extracellular Signal-Regulated MAP Kinases
- GTP Phosphohydrolases
- NRAS protein, human
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Topics |
- Apoptosis
(drug effects)
- Cell Cycle Checkpoints
(drug effects)
- Cell Cycle Proteins
(metabolism)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cell Survival
(drug effects)
- Down-Regulation
(drug effects)
- ErbB Receptors
(metabolism)
- Extracellular Signal-Regulated MAP Kinases
(metabolism)
- GTP Phosphohydrolases
(genetics, metabolism)
- HSP90 Heat-Shock Proteins
(antagonists & inhibitors, metabolism)
- Humans
- Immunoblotting
- Inhibitory Concentration 50
- Melanoma
(genetics, metabolism, pathology)
- Membrane Proteins
(genetics, metabolism)
- Mutation
- Phosphorylation
(drug effects)
- Proto-Oncogene Proteins B-raf
(genetics, metabolism)
- Proto-Oncogene Proteins c-akt
- Receptor, IGF Type 1
(metabolism)
- Skin Neoplasms
(genetics, metabolism, pathology)
- Triazoles
(pharmacology)
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