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Originally published In Press as doi:10.1167/iovs.08-2623 on December 5, 2008
 (Investigative Ophthalmology and Visual Science. 2009;50:1819-1823.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-2623
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Antitumor Activity of Arsenic Trioxide on Retinoblastoma: Cell Differentiation and Apoptosis Depending on Arsenic Trioxide Concentration

Jeong Hun Kim,1,2,3 Jin Hyoung Kim,1,2,3 Young Suk Yu,1,2 Dong Hun Kim,4 Chong Jai Kim,5 and Kyu-Won Kim6

1From the Departments of Ophthalmology and 5Pathology, Seoul National University College of Medicine, Seoul, Korea; 2Seoul Artificial Eye Center, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea; 4Department of Radiology, College of Medicine, Soonchunhyang University, Bucheon, Korea; and the 6Neurovascular Coordination Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.

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 H2O2 production was investigated with the cell-permeable fluorescent dye 2'7'-dichlorofluorescein-diacetate, and the relationship of ATO-induced H2O2 production with caspase-3–dependent apoptosis was validated by Western blot and 4'6-diamidino-2-phenolindole staining, which wwas 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 (≤1 µM), ATO induced the differentiation of retinoblastoma cells through ERK1/2 activation, whereas ROS generation by a high dose (≥2 µM) 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.






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