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E. A. Person, A. K. Samadi, M. S. Cohen; Inhibition of Uveal Melanoma in vitro by a Novel Heat Shock Factor 1 Inhibitor. Invest. Ophthalmol. Vis. Sci. 2010;51(13):870.
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Uveal melanoma is a relatively rare cancer, occurring in 6-7 per million population in the U.S., but with a poor 5-year survival of 30-50% depending on the size of tumor at presentation and presence of metastases. These tumors demonstrate upregulation of the MAP Kinase pathway stimulating the cell cycle and proliferation. Heat shock proteins directly influence this MAP Kinase pathway by serving as chaperone proteins for RAF and RAS and are attractive therapeutic targets since HSPs are overexpressed in melanomas and other tumor cells. Withaferin-A, a natural product withanolide, is a potential treatment for uveal melanoma as it is a novel Heat Shock Factor-1 inhibitor and leads to down-regulation of HSP 90 without significant toxicity in normal cells.
Human uveal melanoma cell lines Mel-290 and OMM-2.3 cells were grown in culture under standard conditions and treated with Withaferin-A at concentrations of 50nM to 20 uM.
Using the MTS assay to determine cell proliferation and cytotoxicity, a significant response to the Withaferin-A was found with IC50 levels in these cells ranging from 0.993 uM to 2.46 uM.
Withaferin A is a novel HSF-1 inhibitor which blocks proliferation of uveal melanoma cells with IC50 levels in the low micromolar range. Further mechanistic investigation in vitro and efficacy studies in vivo will confirm its effectiveness as a novel therapy in this disease.
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