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Antitumor activity of arsenic trioxide on retinoblastoma: cell differentiation and apoptosis depending on arsenic trioxide concentration

Cited 11 time in Web of Science Cited 13 time in Scopus
Authors
Kim, Jeong Hun; Kim, Jin Hyoung; Yu, Young Suk; Kim, Dong Hun; Kim, Chong Jai; Kim, Kyu-Won
Issue Date
2008-12-09
Publisher
Association for Research in Vision and Ophthalmology (ARVO)
Citation
Invest Ophthalmol Vis Sci. 2009;50(4):1819-1823
Keywords
AnimalsAntineoplastic Agents/*administration & dosage/pharmacologyApoptosis/*drug effectsArsenicals/*administration & dosage/pharmacologyBlotting, WesternCaspase 3/metabolismCell CycleCell Differentiation/*drug effectsCell Proliferation/drug effectsFlow CytometryHumansHydrogen Peroxide/metabolismMiceMice, Inbred BALB CMice, Inbred C57BLMitogen-Activated Protein Kinase 1/metabolismMitogen-Activated Protein Kinase 3/metabolismOxides/*administration & dosage/pharmacologyPhosphorylationRetinal Neoplasms/drug therapy/*pathologyRetinoblastoma/drug therapy/*pathologyTumor Cells, Cultured
Abstract
PURPOSE: Arsenic trioxide (ATO) targets multiple pathways in malignant cells, resulting in the promotion of differentiation or in the induction of apoptosis. The antitumor activity of ATO on retinoblastoma was investigated. METHODS: Human retinoblastoma cells were incubated with various ATO concentrations. The antiproliferative effect of ATO was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the effect of ATO on cell-cycle progression was validated by flow cytometry. At a low concentration, the ATO-induced differentiation of retinoblastoma cells was evaluated by neurofilament expression and extracellular signal-regulated kinase (ERK)1/2 activation, which was confirmed by the inhibition of ERK1/2. At a high concentration, ATO-induced H(2)O(2) production was investigated with the cell-permeable fluorescent dye 2'7'-dichlorofluorescein-diacetate, and the relationship of ATO-induced H(2)O(2) production with caspase-3-dependent apoptosis was validated by Western blot and 4'6-diamidino-2-phenolindole staining, which was confirmed by reactive oxygen species (ROS) inhibition. The effect of ATO on tumor formation was assessed with an orthotopic animal model of retinoblastoma. RESULTS: The antitumor activity of ATO in retinoblastoma was related to two main mechanisms, differentiation and apoptosis, which were determined by the level of ATO. At a low dose (or= 2 microM) of ATO induced apoptosis in retinoblastoma cells. Moreover, ATO at low and high doses effectively inhibited tumor formation. CONCLUSIONS: These results suggest that ATO can be used as an effective alternative therapeutic for the treatment of retinoblastoma.
ISSN
1552-5783 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19060284

http://www.iovs.org/cgi/reprint/50/4/1819.pdf

http://hdl.handle.net/10371/68223
DOI
https://doi.org/10.1167/iovs.08-2623
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College of Medicine/School of Medicine (의과대학/대학원)Ophthalmology (안과학전공)Journal Papers (저널논문_안과학전공)
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