Treating retinoblastoma in tissue culture and in a rat model with a novel isoquinoline derivative.

Abstract

PURPOSE. To investigate the effectiveness of a novel isoquinoline derivative, EDL-155, in killing retinoblastoma in vitro and in vivo. METHODS. 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. RESULTS. EDL-155 appeared to destroy the retinoblastoma cells in vitro with an EC(50) of 9.1 micriM. 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. CONCLUSIONS. 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.

• Authors: Mohamed Nassr, Xiangdi Wang, Suchareeta Mitra, Natalie E Freeman-Anderson, Renukadevi Patil, C Ryan Yates, Duane D Miller, Eldon E Geisert
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 51 Issue 7 Pg. 3813-9 (Jul 2010) ISSN: 1552-5783 [Electronic] United States
• PMID: 20570997 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• EDL-155
• Tetrahydroisoquinolines

Topics

• Animals
• Animals, Newborn
• Antineoplastic Agents (therapeutic use)
• Autophagy
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Humans
• Immunoblotting
• Injections
• Microscopy, Confocal
• Mitochondria (ultrastructure)
• Neoplasm Transplantation
• Rats
• Rats, Sprague-Dawley
• Retinal Neoplasms (drug therapy, ultrastructure)
• Retinoblastoma (drug therapy, ultrastructure)
• Tetrahydroisoquinolines (therapeutic use)
• Tumor Cells, Cultured