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D. Faingold, J.–C. Marshall, S. Bakalian, A. Al–Kandari, C. Edelstein, M.N. Burnier, Jr.; Immune Expression and Inhibition of Hsp90 in Human Uveal Melanoma . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2247.
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© ARVO (1962-2015); The Authors (2016-present)
Up–regulation of heat shock protein 90 (Hsp90), a molecular chaperone, has been described in different neoplasms. The Geldanamycine derivative, 17–allylamino–17–demethoxygeldanamycin (17–AAG), has been shown to inhibit Hsp90 and its target proteins. The goal of this study is to examine the immunohistochemical profile of Hsp90 and its association with prognostic features in uveal melanoma. In addition we aim to determine whether uveal melanoma cells are sensitive to the cytotoxic effects of 17–AAG.
Thirty–five paraffin–embedded sections of primary human uveal melanoma were obtained from the Henry C. Witelson Ocular Pathology Registry. Hsp90 expression was determined by avidin–biotin complex (ABC) immunohistochemistry method and scored semi quantitatively. Hsp90 expression in four uveal melanoma cell lines ( 92.1, OCM–1, MKTBR and SP6.5) was verified by imunocytochemical analysis of cytospin sections. A Sulfurhodamine–B based proliferation assay was used to compare uveal melanoma cell growth with a range of concentrations of 17–AAG. The averaged results per condition were recorded. The Student's t–test was used to compare results from cells cultured with and without 17– AAG.
Immunohistochemical expression of Hsp90 was identified in 20 (57 %) of the paraffin embedded sections from uveal melanoma patients. The expression of the Hsp90 was significantly associated with largest tumor dimension, in the Hsp90 positive tumors (p=0.01). The four human uveal melanoma cell lines were positive for Hsp90 expression by immunocytochemical analysis. When 17– AAG was added to the cell lines, a statistically significant reduction on proliferation rate of uveal melanoma cell lines was observed with concentrations of 100 uM to 1 uM.
The immunohistochemical expression of Hsp90 in uveal melanoma indicates worse prognosis. To the best of our knowledge this is the first report showing the inhibitory effect on proliferation of uveal melanoma cells using 17–AAG to target Hsp90. Therefore Hsp90 may be used as a potential target for local and systemic treatment of patients with uveal melanomas. Further trials in uveal melanoma models should be undertaken to study the effect of 17–AAG in vivo.
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