May 2003
Volume 44, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2003
Fenretinide Induces Apoptosis in Human Retinal Pigment Epithelial (RPE) Cells: The Role of Retinoid Receptors
Author Affiliations & Notes
  • W. Samuel
    Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, United States
  • R.K. Kutty
    Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, United States
  • R.A. Chandraratna
    Departments of Chemistry and Biology, Retinoid Research, Allergan Pharmaceuticals, Irvine, CA, United States
  • B. Wiggert
    Departments of Chemistry and Biology, Retinoid Research, Allergan Pharmaceuticals, Irvine, CA, United States
  • Footnotes
    Commercial Relationships  W. Samuel, None; R.K. Kutty, None; R.A.S. Chandraratna, Allergan Pharmaceuticals E; B. Wiggert, None.
  • Footnotes
    Support  none
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 4548. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Abstract: : 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.

Keywords: retinal pigment epithelium • retinoids/retinoid binding proteins • apoptosis/cell death 
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