Molecular sequelae of histone deacetylase inhibition in human retinoblastoma cell lines: Clinical implications Journal Article
| Authors: | Poulaki, V.; Mitsiades, C. S.; Kotoula, V.; Negri, J.; McMullan, C.; Miller, J. W.; Marks, P. A.; Mitsiades, N. |
| Article Title: | Molecular sequelae of histone deacetylase inhibition in human retinoblastoma cell lines: Clinical implications |
| Abstract: | 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-celllymphoma. 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-κB 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 vorinostatinduced apoptosis. Vorinostat downregulated baseline NF-κB activity and potentiated the activity of the DNAdamaging 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-κB 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. © Association for Research in Vision and Ophthalmology. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; genetics; histone deacetylase inhibitor; doxorubicin; cancer growth; drug efficacy; drug potentiation; flow cytometry; cell proliferation; metabolism; cell cycle; reverse transcription polymerase chain reaction; apoptosis; enzyme inhibition; gene expression profiling; neoplasm proteins; notch receptor; immunoglobulin enhancer binding protein; cell differentiation; caspase 3; cancer cell culture; enzyme activation; in vitro study; retinoblastoma; enzymology; pathology; retina tumor; retinal neoplasms; enzyme inhibitor; caspase; caspases; cell line, tumor; protein p53; drug synergism; extracellular matrix; cancer inhibition; drug antagonism; messenger rna; reverse transcriptase polymerase chain reaction; enzyme inhibitors; histone; nf-kappa b; tumor protein; tumor cell line; immunoblotting; vorinostat; hydroxamic acids; tumor suppressor protein p53; down regulation; caspase 8; caspase 9; cell metabolism; histones; histone deacetylases; hydroxamic acid; histone deacetylase; acetylation; carboxycinnamic acid bishydroxamide; ephrin; broxuridine; cinnamic acid derivative; bromodeoxyuridine; cinnamates |
| Journal Title: | Investigative Ophthalmology & Visual Science (IOVS) |
| Volume: | 50 |
| Issue: | 9 |
| ISSN: | 0146-0404 |
| Publisher: | Association for Research in Vision and Ophthalmology |
| Date Published: | 2009-09-01 |
| Start Page: | 4072 |
| End Page: | 4079 |
| Language: | English |
| DOI: | 10.1167/iovs.09-3517 |
| PUBMED: | 19387079 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Export Date: 30 November 2010" - "CODEN: IOVSD" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work