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.

Untangling knots between autophagic targets and candidate drugs, in cancer therapy

“…Imipramine exerts anti‐tumour effects on glioma cells by inducing autophagic cell death through inhibiting PI3K/Akt/mTOR signalling . Other drugs and chemical compounds, including sulphinosine, Cordyceps militaris (CM), concanavalin‐A, EDL‐291, curcumin and bromopyruvate, have also been reported to be capable of inducing autophagy in GBM . However, the role of autophagy in these cases requires further study.…”

New substituted 4H-chromenes as anticancer agents

“…We have explored various pharmacophores such as 1,2,3,4-THI analogs (known as EDL compounds), 2-arylthiazolidine-4-carboxylic acid amides (ATCAA), 2-aryl-4-benzoylimidazoles (ABI), and 4-substituted methoxybenzoyl-arylthiazole (SMART) for glioma, melanoma and prostate cancers. 2-9 …”