Abstract | PURPOSE: To evaluate the potential of proteasome inhibitors, a novel class of antitumor agents, for the treatment of retinoblastoma. The proteasome inhibitor bortezomib ( PS-341, Velcade; Millennium Pharmaceuticals, Cambridge, MA), approved by the US Food and Drug Administration for the treatment of multiple myeloma, is being studied for the treatment of several other malignancies. Among other effects, it inactivates the transcription factor nuclear factor-kappaB ( NF-kappaB) by blocking the degradation of its inhibitor, IkappaB. NF-kappaB, which is constitutively active in human retinoblastoma cells and promotes their survival, represents a therapeutic target for patients with this malignancy. METHODS: RESULTS: CONCLUSIONS:
Bortezomib induces a stress response and triggers caspase-dependent apoptosis in human retinoblastoma cells at clinically achievable concentrations. This study provides insight into the molecular mechanism(s) of the antitumor activity of bortezomib and a basis for future preclinical studies leading to clinical trials of bortezomib, alone or in combination with conventional chemotherapy, to improve patient outcomes in retinoblastoma.
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Authors | Vassiliki Poulaki, Constantine S Mitsiades, Vassiliki Kotoula, Joseph Negri, Douglas McMillin, Joan W Miller, Nicholas Mitsiades |
Journal | Investigative ophthalmology & visual science
(Invest Ophthalmol Vis Sci)
Vol. 48
Issue 10
Pg. 4706-19
(Oct 2007)
ISSN: 0146-0404 [Print] United States |
PMID | 17898295
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Biomarkers, Tumor
- Boronic Acids
- Formazans
- Indicators and Reagents
- Neoplasm Proteins
- Protease Inhibitors
- Pyrazines
- Tetrazolium Salts
- MTT formazan
- Bortezomib
- Caspases
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Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Biomarkers, Tumor
(genetics, metabolism)
- Boronic Acids
(pharmacology)
- Bortezomib
- Caspases
(metabolism)
- Cell Proliferation
(drug effects)
- Flow Cytometry
- Formazans
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Humans
- Immunoblotting
- Indicators and Reagents
- Neoplasm Proteins
(genetics, metabolism)
- Oligonucleotide Array Sequence Analysis
- Protease Inhibitors
(pharmacology)
- Pyrazines
(pharmacology)
- Retinal Neoplasms
(genetics, metabolism, pathology)
- Retinoblastoma
(genetics, metabolism, pathology)
- Reverse Transcriptase Polymerase Chain Reaction
- Tetrazolium Salts
- Tumor Cells, Cultured
- Up-Regulation
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