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J. Elison, N. Claros, L. Vassilev, T.C. Lee; Small Molecule Induction of P53–Mediated Apoptosis in Choroidal Melanoma . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2223.
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To determine whether small molecule inhibition of p53 degradation leads to p53–mediated apoptosis in a highly invasive choroidal melanoma cell line.
The M619 cell line was treated with Nutlin 3A, a small molecule designed to inhibit binding of p53 to its regulator, HDM–2. Trypan blue cell viability assays, western blot analyses, and confocal microscopy were performed to determine the effects of Nutlin 3A on cell survival and on protein levels of p53 and its downstream targets.
The small molecule Nutlin 3A caused dose–dependent cell death in the micromolar range in choroidal melanoma cells. Complete cell death was acheived at 5 days with a 10 uM concentration of Nutlin 3A. Protein levels of p53 and its downstream targets, p21 and HDM–2, were increased after treatment with 1 uM, 5 uM and 10 uM Nutlin 3A in a dose–dependent fashion. In contrast, treatment with Nutlin 3B, the less potent enantiomer of Nutlin 3A, demonstrated minimal effects on cell viability and no upregulation of p53 or of its downstream targets.
Nutlin 3A induces p53–mediated apoptosis in a highly invasive choroidal melanoma cell line. Nutlin 3A or a similar molecule may provide a future treatment option for prophylaxis and/or treatment for metastatic choroidal melanoma in a non–genotoxic manner.
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