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Cell Cycle, Cell Death, and Senescence

Glioma Regression In vitro and In vivo by a Suicide Combined Treatment

Department of Molecular Biology, Centro de Biología Molecular Severo Ochoa, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain

Requests for reprints: Marta Izquierdo, Department of Molecular Biology, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid, Cantoblanco c/ Nicolás Cabrera no. 1, 28049 Madrid, Spain. Phone: 34-91-1964569; Fax: 34-91-1964420; E-mail: mizquierdo{at}cbm.uam.es

We present here a suicide therapy against malignant gliomas based on the transfer to tumor cells of a gene encoding a β-glucosidase, linamarase (lis), which in the presence of the innocuous substrate linamarin (lin) produces cyanide, blocking the mitochondrial respiratory chain. Dog glioma cells carrying the lis gene are thus sensitive to lin (IC₅₀ of 250 µg/mL at 48 hours) and cell death is accompanied by mitochondrial fission and ATP depletion. The combination of lis/lin with an otherwise nontoxic level of glucose oxidase (GO) enhances the therapeutic potential (IC₅₀ of 50 µg/mL at 48 hours). GO produces hydrogen peroxide, inducing oxidative damage and increasing cellular stress. We show here the antitumoral effect of the lis/lin/GO therapy in a canine glioma cell line and in a xenograft glioma model in nude mice. The synergic combination causes mitochondrial membrane depolarization and phosphatidylserine externalization and accelerates death by 48 hours. The lethal process is caspase independent; poly(ADP-ribose) polymerase 1 is not implicated; and there is no apoptosis-inducing factor translocation to the nucleus. The combined system induces autophagic cell death that can be rescued by 3-methyladenine and is characterized by the presence of double-membrane vesicles and punctate LC-3 pattern. (Mol Cancer Res 2008;6(3):407–17)