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W. Samuel, R.K. Kutty, R.A. Chandraratna, B. Wiggert; Fenretinide Induces Apoptosis in Human Retinal Pigment Epithelial (RPE) Cells: The Role of Retinoid Receptors . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4548.
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Purpose: Retinoic acid (RA) is a known regulator of many cellular functions including proliferation and differentiation. Its actions are mediated through a signaling pathway involving nuclear receptors, RAR and RXR. Fenretinide, N-(4-hydoxyphenyl)retinamide, a retinoic acid derivative and a potential cancer preventive agent, is known to induce apoptosis in cancer cells. Long term administration of fenretinide has been shown to lower plasma retinol levels and affect night vision. Recent studies from our laboratory have shown that low concentrations of fenretinide induce differentiation of cultured human retinal pigment epithelial cells into a neuronal phenotype (Chen et al., J.Neurochem, in press). The present study is aimed at assessing the toxic effect of fenretinide on human retinal pigment epithelial cells. Methods: Human RPE cells (ARPE-19) in culture were treated with 1-20 µM fenretinide in the presence or absence of retinoid receptor antagonists for various time intervals. Cell lysates were used to measure the progression of apoptosis by a sandwich-enzyme immunoassay using anti-histone antibody directed against mono-and oligonucleosomes. Activities of caspases, 2, 3, 8 and 9, a family of cysteine proteases involved in apoptosis, were measured using a fluorimetric method. Results: Fenretinide induced apoptosis in ARPE-19 cells in a dose- and time-dependent manner as indicated by the generation of mono- and oligonucleosomes. AGN194301, a RARα receptor specific antagonist, effectively blocked the apoptosis. Retinoid receptor pan-antagonist, AGN194310 and AGN193109 also showed this effect. Fenretinide induced apoptosis was accompanied by a marked increase in caspase-2 and caspase-3 activities. Conclusions: We have shown for the first time that fenretinide induces apoptosis in ARPE-19 cells and that RARα is involved in this process.
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