HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplementary Table All Versions of this Article: iovs.09-3517v1 50/9/4072    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Poulaki, V. Articles by Mitsiades, N. Search for Related Content PubMed PubMed Citation Articles by Poulaki, V. Articles by Mitsiades, N.

Molecular Sequelae of Histone Deacetylase Inhibition in Human Retinoblastoma Cell Lines: Clinical Implications

¹From the Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; ²Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; ³Department of Pathology, School of Medicine, Thessaloniki, Greece; and ⁴Memorial Sloan-Kettering Cancer Center, New York, New York.

PURPOSE. To characterize the molecular sequelae induced in retinoblastoma (Rb) cells by histone deacetylase inhibitors (HDACIs). Hydroxamic acid-based HDACIs such as vorinostat (suberoylanilide hydroxamic acid) induce the differentiation and apoptosis of transformed cells. Vorinostat has demonstrated significant anticancer activity against hematologic and solid tumors at doses well tolerated by patients and has been approved for the treatment of patients with cutaneous T-cell lymphoma.

METHODS. The authors evaluated the effects of the HDACIs vorinostat and m-carboxycinnamic acid bis-hydroxamide on the Rb cell lines Y79 and WERI-Rb1 with the use of the MTT assay, BrdU incorporation assay, flow cytometry, immunoblotting, gene-expression profiling, quantitative RT-PCR, and NF-B DNA-binding assay.

RESULTS. Both HDACIs were effective against both Rb cell lines, inducing growth arrest and apoptosis in vitro. Vorinostat increased p53 expression and activated caspases -8, -9 and -3, whereas caspase inhibition abrogated vorinostat-induced apoptosis. Vorinostat downregulated baseline NF-B activity and potentiated the activity of the DNA-damaging chemotherapeutic doxorubicin. Gene expression profiling and qRT-PCR demonstrated that vorinostat modulated the mRNA levels of genes important for signal transduction, cell cycle, cellular metabolism, stress response, apoptosis, extracellular matrix synthesis, and cell differentiation. Notably, several transcripts involved in the ephrin and Notch signaling pathways were upregulated.

CONCLUSIONS. HDACIs, such as vorinostat, induce caspase-dependent apoptosis in Rb cells, downregulate baseline NF-B activity, and potentiate the effectiveness of conventional chemotherapy. The finding that vorinostat augments the effectiveness of doxorubicin provides a rationale for future clinical studies looking at the use of vorinostat in combination with conventional chemotherapy in Rb.