[Targeting the gene of glucose metabolism for the treatment of advanced gliomas].
Loss of chromosomes is a recurrent event in cancer. Chromosome-10 losses occur with tumor progression and characterize advanced gliomas. This chromosome carries many genes involved in glucose metabolism. Hexokinase (HK) gene is located on chromosome-10. Hexokinase enzymatic activity is decreased in glioblastomas. Hexokinase enables glucose entry into glycolysis and is critical for these highly glycolytic tumors. These enzyme is either free in the cytosol or bound to the mitochondrial outer membrane. Disturbance of HK binding to mitochondria by lonidamine led to inhibition of cells and xenografted-glioma growth. Hexokinase bind to a mitochondrial porin which involved peripheral benzodiazepine receptors. Inhibition of HK and peripheral benzodiazepine receptors by lonidamine and diazepam led to synergistic antitumoral activity in xenografted gliomas. Co-inhibition of these two receptors will lead to a decrease in glycolysis, often elevated in these tumors, without modifying energetic metabolism of normal cells.
Oudard
S
S
Unité mixte de recherche 147 CNRS, Paris.
Miccoli
L
L
Dutrillaux
B
B
Poupon
M F
MF
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002872:Chromosome Deletion; D003975:Diazepam / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis / Q000235:genetics; D006593:Hexokinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D008928:Mitochondria / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018272:Porins / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007191:Indazoles; D009363:Neoplasm Proteins; D018272:Porins; D006593:Hexokinase; D005947:Glucose; D003975:Diazepam; C016371:lonidamine