Treating retinoblastoma in tissue culture and in a rat model with a novel isoquinoline derivative
| Autor: | XiangDi Wang, Suchareeta Mitra, Mohamed A. Nassr, Duane D. Miller, Eldon E. Geisert, Renukadevi Patil, Natalie E. Freeman-Anderson, C. Ryan Yates |
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| Rok vydání: | 2010 |
| Předmět: |
Autophagosome
animal structures Retinal Neoplasms Immunoblotting Antineoplastic Agents Vacuole Injections Rats Sprague-Dawley chemistry.chemical_compound Tissue culture In vivo Tetrahydroisoquinolines medicine Autophagy Tumor Cells Cultured Animals Humans Microscopy Confocal Dose-Response Relationship Drug Chemistry Retinoblastoma musculoskeletal neural and ocular physiology Acridine orange musculoskeletal system medicine.disease Molecular biology eye diseases In vitro Staining Mitochondria Rats Disease Models Animal Biochemistry Animals Newborn tissues Neoplasm Transplantation |
| Zdroj: | Investigative ophthalmologyvisual science. 51(7) |
| ISSN: | 1552-5783 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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