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V. Poulaki, V. Kotoula, C. S. Mitsiades, J. Negri, J. W. Miller, S. Mukai, N. Mitsiades; Antitumor Effects of the Histone Deacetylase Inhibitor Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Human Retinoblastoma Cell Lines: Therapeutic Implications. Invest. Ophthalmol. Vis. Sci. 2008;49(13):26.
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To characterize the mechanism of apoptosis induced in retinoblastoma (Rb) by the histone deacetylase inhibitor (HDACI) vorinostat (suberoylanilide hydroxamic acid). HDACIs are promising and novel anticancer agents that are already being used clinically. Vorinostat has demonstrated significant anticancer activity in clinical trials against both hematologic and solid tumors at doses well tolerated by patients and has been approved for treatment of cutaneous T-cell lymphoma. We have previously reported that vorinostat induces 1. growth arrest and apoptosis in Rb cell lines in vitro, 2. downregulation of anti-apoptotic Bcl-2, 3. upregulation of pro-apoptotic Bax, and 4. cleavage of Bid.
We evaluated the effect of vorinostat on the Rb cell lines Y79 and WERI-Rb1 using the MTT assay, gene-expression profiling, quantitative RT-PCR (with TaqMan® assays from Applied Biosystems, Foster City, CA), and an assay for NF-ΚB activity (Active Motif, Carlsbad, CA).
Gene-expression profiling and qRT-PCR demonstrated that vorinostat modulated the mRNA levels for genes important for signal transduction, cell cycle, cellular metabolism, stress response, apoptosis, extracellular matrix synthesis, and control of cell differentiation. Notably, several transcripts involved in the ephrin and Notch signaling pathways were upregulated. Treatment with vorinostat led to activation of caspases -8 and -3, whereas the pan-caspase inhibitor ZVAD-FMK abrogated vorinostat-induced apoptosis. Vorinostat downregulated baseline NF-ΚB activity and potentiated the activity of the DNA-damaging chemotherapeutic agent doxorubicin.
HDACIs, such as vorinostat, induce caspase-dependent apoptosis in Rb cells and downregulate baseline NF-ΚB activity. As NF-ΚB is constitutively active in human Rb cell lines and promotes survival of these cells (Poulaki et al, Am J Pathol. 2002;161(6):2229-40), vorinostat may potentiate the response of Rb cells to other apoptotic stimuli. Our finding that vorinostat augments the effectiveness of doxorubicin provides a rationale for future studies looking at the use of vorinostat in combination with conventional chemotherapy in treatment of Rb.
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