May 2003
Volume 44, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2003
Histone Deacetylase Inhibitors (HDACIs), Inhibit Proliferation and Induce Apoptosis of Primary and Metastatic Uveal Melanoma Cell Lines in vitro: A Potential Therapeutic Strategy for Uveal Melanoma (UM)
D.D. Klisovic; M.I. Klisovic; S.E. Katz; D. Effron; J. Wickham; M.R. Parthun; G. Marcucci
Author Affiliations & Notes
  • D.D. Klisovic
    Ophthalmology, Ohio State University, Columbus, OH, United States
  • M.I. Klisovic
    Ophthalmology, Ohio State University, Columbus, OH, United States
  • S.E. Katz
    Ophthalmology, Ohio State University, Columbus, OH, United States
  • D. Effron
    Ophthalmology, Ohio State University, Columbus, OH, United States
  • J. Wickham
    Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH, United States
  • M.R. Parthun
    Molecular and Cellular Biochemistry, Ohio State University, Columbus, OH, United States
  • G. Marcucci
    Internal Medicine, Ohio State University, Columbus, OH, United States
  • Footnotes
    Commercial Relationships  D.D. Klisovic, None; M.I. Klisovic, None; S.E. Katz, None; D. Effron, None; J. Wickham, None; M.R. Parthun, None; G. Marcucci, None.
  • Footnotes
    Support  Ohio Lions Eye Res. Foundation
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 4977. doi:
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      D.D. Klisovic, M.I. Klisovic, S.E. Katz, D. Effron, J. Wickham, M.R. Parthun, G. Marcucci; Histone Deacetylase Inhibitors (HDACIs), Inhibit Proliferation and Induce Apoptosis of Primary and Metastatic Uveal Melanoma Cell Lines in vitro: A Potential Therapeutic Strategy for Uveal Melanoma (UM) . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4977.

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Abstract

Abstract: : Purpose: UM is the most common primary malignant ocular tumor in adults. No effective chemotherapy regimens are available for either intraocular or metastatic UM. We tested the ability of HDACIs sodium butyrate (NaB), trichostatin (TSA) and depsipeptide (DP) to inhibit proliferation and induce apoptosis in UM cells in vitro. Methods: 3 primary and 2 metastatic (liver metastasis) UM cell lines were treated with NaB, TSA and DP for 48 hours. Cell proliferation was studied by MTT-based proliferation assay. Induction of apoptosis was studied by flow-cytometry. Changes in gene expression of Fas/FasL, p21 and p27 were studied by RT-PCR and changes in gene expression of Bcl-2/Bax by Real-time PCR. Histone acetylation (H3 and H4), Fas/FasL, p21, p27, bcl-2/bax and caspase-3 protein levels were determined by Western-blot and ELISA assayResults: Dose-dependent increase in histone (H3 and H4) acetylation was observed in all UM cell lines. Single pulse of HDACIs strongly inhibited cell growth in all primary and metastatic cell lines (range of 60-90% inhibition). Flow cytometry revealed significant induction of apoptosis (~ 3.8-fold increase). RT-PCR and Western-blot revealed dose-dependent up-regulation Fas/FasL, p21 and p27 proteins. A 5.6-fold increase in caspase-3 activity was observed. This increase could be inhibited by protein synthesis inhibitor cycloheximide. No changes in Bcl-2/Bax gene expression were detected by Real-time PCR or Western-blot. Conclusions: HDACIs are potent inhibitors of primary and metastatic UM cell growth in vitro. In addition, they strongly induce apoptosis in those cell lines. Our data suggest that inhibition of cell growth is mediated via the increase in p21 and p27 expression and induction of apoptosis via the Fas/FasL signaling pathway. Bcl-2/Bax signaling pathway does not seem to be involved in HDAC-induced apoptosis in UM cell lines. HDACIs may prove to be a valuable adjunctive treatment modality for primary and metastatic UM.

Keywords: melanoma • apoptosis/cell death • oncology 
© 2003, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.
Copyright © 2025 Association for Research in Vision and Ophthalmology.
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