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V. Poulaki, A. Joussen, E. Iliaki, C.S. Mitsiades, G. Fanourakis, N. Mitsiades; The Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) Induces Growth Arrest and Apoptosis in Human Retinoblastoma Cell Lines . Invest. Ophthalmol. Vis. Sci. 2003;44(13):931.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To evaluate the role of histone deacetylase (HDAC) inhibitors in the treatment of retinoblastoma (Rb). Histone acetylation plays a role in transcriptional regulation, probably by altering chromatin structure. Transcriptionally silent chromatin is composed of nucleosomes in which the histones have low levels of acetylation on lysine residues of their amino-terminal tails. Acetylation of core nucleosomal histones is regulated by the opposing activities of histone acetyltransferases (HATs) and HDACs. Acetylation of histone proteins neutralizes the positive charge on lysine residues, thereby permitting unfolding of the associated DNA, access by transcription factors, and consequent changes in gene expression. Hydroxamic acid-based hybrid polar compounds that inhibit HDACs cause the accumulation of acetylated core nucleosomal histones in cultured cells, and induce differentiation and/or apoptosis of transformed cells. The growth-suppressive and apoptotic activity of these agents is generally restricted to transformed cells and, thus, HDAC inhibitors (HDACIs) represent promising novel anticancer agents, and clinical evaluation of these agents is underway. Methods: Since sodium butyrate, a compound with HDACI activity, induces apoptosis in Rb cells in vitro, we evaluated the effect of suberoylanilide hydroxamic acid (SAHA), the prototype of a series of potent hydroxamic acid-based HDACIs, on the Rb cell lines Y79 and WERI-Rb1 using BrdU incorporation assays and cell cycle analysis by propidium iodide (PI). Protein expression and cleavage was analyzed by immunoblotting analysis. Results: SAHA induced growth arrest in both Rb cell lines, followed by induction of apoptosis. SAHA increased acetylated histone levels and p53 expression in Y79 cells and resulted in cleavage of PARP, indicating an apoptotic mechanism. SAHA also induced cleavage of caspase-9 and caspase-3, as well as downregulation of the anti-apoptotic Bcl-2, upregulation of the pro-apoptotic Bax, and cleavage of Bid. Conclusions: Histone deacetylase inhibitors, such as SAHA, induce apoptosis in Rb cells via an apoptotic pathway. Since Phase I clinical studies have demonstrated that SAHA is bioavailable, well-tolerated and bioactive after oral administration, it represents a promising novel agent for the treatment of patients with Rb.
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