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Mohamed Nassr, XiangDi Wang, Suchareeta Mitra, Natalie E. Freeman-Anderson, Renukadevi Patil, C. Ryan Yates, Duane D. Miller, Eldon E. Geisert; Treating Retinoblastoma in Tissue Culture and in a Rat Model with a Novel Isoquinoline Derivative. Invest. Ophthalmol. Vis. Sci. 2010;51(7):3813-3819. doi: 10.1167/iovs.09-5042.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the effectiveness of a novel isoquinoline derivative, EDL-155, in killing retinoblastoma in vitro and in vivo.
Dose-response curves were generated in which Y79 retinoblastoma cells tagged with luciferase (Y79-Luc) were treated with serial concentrations of EDL-155. Electron microscopy was used to evaluate the ultrastructural morphology of EDL-155–treated Y79 cells. To determine whether autophagy was induced in EDL-155–treated Y79-Luc cells, staining with acridine orange and LC-3 immunoblot analysis was performed. To evaluate the efficacy of EDL-155 in vivo, Y79-Luc retinoblastoma cells were injected into the vitreous cavity of newborn rats, followed by periocular injections of EDL-155 (20 mg/kg/day) or an equivalent dosage of saline.
EDL-155 appeared to destroy the retinoblastoma cells in vitro with an EC50 of 9.1 μM. EDL-155–treated retinoblastoma cells displayed a lack of viable mitochondria and the presence of autophagosomes wrapped in the characteristic double membranes. Acridine orange staining of EDL-155–treated retinoblastoma cells demonstrated the accumulation of vacuoles, and the immunoblots displayed a shift in molecular weight of LC-3, indicative of incorporation into autophagosome vesicles. In the retinoblastoma animal model, four doses of EDL-155 were delivered over 4 days, which was sufficient to see a significant decrease (P = 0.01) in viable intraocular tumors. Seven of the 25 rats treated with EDL-155 had no detectable living tumor. No significant decrease in viable tumor was observed in control animals.
EDL-155 appears to eliminate retinoblastoma cells by disrupting mitochondria and inducing autophagy. Local delivery of EDL-155 may be an effective therapy for some types of ocular cancers.
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