Glioma regression in vitro and in vivo by a suicide combined treatment.

Full Abstract

We present here a suicide therapy against malignant gliomas based on the transfer to tumor cells of a gene encoding a beta-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 (IC(50) of 250 microg/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 (IC(50) of 50 microg/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.

Author information

Author/s: García-Escudero, Vega (V); Gargini, Ricardo (R); Izquierdo, Marta (M);

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

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Molecular cancer research : MCR (Mol Cancer Res), published in United States. (Language: eng)

Reference: 2008-Mar; vol 6 (issue 3) : pp 407-17

Dates: Created 2008/03/13; Completed 2008/06/03; Revised 2008/11/21;

PMID: 18337448, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt - therapeutic use
Acetylcysteine - therapeutic use
Adenine - analogs & derivatives; therapeutic use
Animals
Brain Neoplasms - pathology; therapy
Cell Death - drug effects

Associated Chemicals: Nitriles (0) ; 1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt (149-45-1) ; 3-methyladenine (5142-23-4) ; linamarin (554-35-8) ; Acetylcysteine (616-91-1) ; Adenine (73-24-5) ; Hydrogen Peroxide (7722-84-1) ; Glucose Oxidase (EC 1.1.3.4)

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