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A novel C-terminal HSP90 inhibitor KU135 induces apoptosis and cell cycle arrest in melanoma cells
Samadi, Abbas K. Zhang, Xuan Mukerji, Ridhwi Donnelly, Alison C. Blagg, Brian S. J. Cohen, Mark S.
Samadi, Abbas K.
Zhang, Xuan
Mukerji, Ridhwi
Donnelly, Alison C.
Blagg, Brian S. J.
Cohen, Mark S.
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Abstract
Heat shock protein 90 (Hsp90) is differentially expressed in tumor cells including melanoma and involved in proper folding, stabilization and regulation of cellular proteins. We investigated a novobiocin-derived Hsp90 C-terminal inhibitor, KU135, for anti-proliferative effects in melanoma cells. The results indicate that KU135 reduced cell viability and cell proliferation in melanoma cells and IC50 values for A735(DRO), M14(NPA), B16F10 and SKMEL28 cells were 0.82, 0.92, 1.33 and 1.30 M respectively. KU135 induced a more potent anti-proliferative effect in most melanoma cells versus N-terminal Hsp90 inhibitor 17AAG. KU135 induced apoptosis in melanoma cells, as indicated by annexin V/PI staining, reduction in the mitochondrial membrane potential, mitochondrial cytochrome C release and caspase 3 activation. KU135 reduced levels of Hsp90 client proteins Akt, BRAF, RAF-1, cyclin B and cdc25 proteins. Additionally, it reduced Hsp70, Hsp90 paralog, GRP94 and HSF1 levels. KU135 induced strong G2/M cell cycle arrest, associated with decreased expression of cdc25c, cyclin B and increased phosphorylation of cdc25c. These finding show that KU135 reduced cell survival, proliferation, and induces apoptosis in melanoma cells. We suggest that KU135 may be a potential candidate for cancer therapy against melanoma.
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Date
2011-12-22
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Elsevier
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Keywords
Hsp90 inhibitor, C-terminal, Melanoma
Citation
Samadi, A. K., Zhang, X., Mukerji, R., Donnelly, A. C., Blagg, B. S., & Cohen, M. S. (2011). A novel C-terminal HSP90 inhibitor KU135 induces apoptosis and cell cycle arrest in melanoma cells. Cancer Letters, 312(2), 158–167. http://doi.org/10.1016/j.canlet.2011.07.031