title: EDL-291, a novel isoquinoline, presents antiglioblastoma effects in vitro and in vivo.
abstract: To investigate the effectiveness of EDL-291, a 6,7-dimethoxy-1-[4-(4-methoxypyridin-3-yl)benzyl]-1,2,3,4-tetrahydroisoquinoline dihydrochloride compound, in inhibiting the survival of glioblastoma in vitro and in vivo. Dose-response curves were generated to determine the EC50 in rat and human glioblastoma cell lines by treatment with different dilutions of EDL-291. To evaluate the architecture of the glioblastoma cells after treatment with EDL-291, the rat and human glioblastoma cells were stained with Mito Tracker Green FM. To determine whether autophagy was induced in EDL-291-treated glioblastoma cells, both rat and human glioblastoma cell lines were stained with acridine orange and light chain-3 immunoblots were performed. The efficacy of EDL-291 was monitored in vivo using a rat glioblastoma model. Rat glioblastoma cells were transplanted into an intracranial rat model, followed by infusions of saline, a low dose of EDL-291 (20 mg/kg for the first half hour, followed by 40 mg/kg EDL-291 in saline for 4 h), or a high dose of EDL-291 (60 mg/kg for the first half hour, followed by 90 mg/kg EDL-291 for 4 h). EDL-291 inhibits glioblastoma in vitro by destroying the mitochondria as shown with Mito Tracker Green FM. Acridine orange staining and light chain-3 immunoblots suggest that autophagy is induced when glioblastoma cells are treated with EDL-291. In vivo, a low dosage of EDL-291 is sufficient and effective in reducing glioblastoma tumor size. EDL-291 selectively induces cell death in rat and human glioblastoma cell lines by the induction of autophagy. EDL-291 exhibits antiglioblastoma effects both in vitro and in vivo.
authors.affiliation: Department of Ophthalmology, Hamilton Eye Institute, College of Medicine, University of Tennessee Health Science Center, Memphis, 38163, USA. xwang17@uthsc.edu
authors.forename: Xiang-Di
authors.initials: XD
authors.lastname: Wang
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Freeman
authors.forename: Renukadevi
authors.initials: R
authors.lastname: Patil
authors.forename: Shivaputra A
authors.initials: SA
authors.lastname: Patil
authors.forename: Suchareeta
authors.initials: S
authors.lastname: Mitra
authors.forename: William E
authors.initials: WE
authors.lastname: Orr
authors.forename: Clint W
authors.initials: CW
authors.lastname: Abner
authors.forename: Charles Ryan
authors.initials: CR
authors.lastname: Yates
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Eldon E
authors.initials: EE
authors.lastname: Geisert
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C574245:EDL-291; D007546:Isoquinolines