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

Mohamed Nassr, Xiangdi Wang, Suchareeta Mitra, Natalie E. Freeman-Anderson, Renukadevi Patil, Charles Yates, Duane Miller, Eldon E. Geisert

Research output: Contribution to journalArticle

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Abstract

Purpose. To investigate the effectiveness of a novel isoquino-line 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 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 autophago-some 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 maybe an effective therapy for some types of ocular cancers.

Original languageEnglish (US)
Pages (from-to)3813-3819
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume51
Issue number7
DOIs
StatePublished - Jul 1 2010

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Retinoblastoma
Acridine Orange
Autophagy
isoquinoline
EDL-155
Mitochondria
Eye Neoplasms
Intraocular Injections
Staining and Labeling
Neoplasms
Vacuoles
Luciferases
Electron Microscopy
Animal Models
Molecular Weight

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Treating retinoblastoma in tissue culture and in a rat model with a novel isoquinoline derivative. / Nassr, Mohamed; Wang, Xiangdi; Mitra, Suchareeta; Freeman-Anderson, Natalie E.; Patil, Renukadevi; Yates, Charles; Miller, Duane; Geisert, Eldon E.

In: Investigative Ophthalmology and Visual Science, Vol. 51, No. 7, 01.07.2010, p. 3813-3819.

Research output: Contribution to journalArticle

Nassr, Mohamed ; Wang, Xiangdi ; Mitra, Suchareeta ; Freeman-Anderson, Natalie E. ; Patil, Renukadevi ; Yates, Charles ; Miller, Duane ; Geisert, Eldon E. / Treating retinoblastoma in tissue culture and in a rat model with a novel isoquinoline derivative. In: Investigative Ophthalmology and Visual Science. 2010 ; Vol. 51, No. 7. pp. 3813-3819.
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abstract = "Purpose. To investigate the effectiveness of a novel isoquino-line 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 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 autophago-some 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 maybe an effective therapy for some types of ocular cancers.",
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AU - Patil, Renukadevi

AU - Yates, Charles

AU - Miller, Duane

AU - Geisert, Eldon E.

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N2 - Purpose. To investigate the effectiveness of a novel isoquino-line 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 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 autophago-some 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 maybe an effective therapy for some types of ocular cancers.

AB - Purpose. To investigate the effectiveness of a novel isoquino-line 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 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 autophago-some 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 maybe an effective therapy for some types of ocular cancers.

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