POTENTIATION OF LONIDAMINE AND DIAZEPAM, 2 AGENTS ACTING ON MITOCHONDRIA, IN HUMAN GLIOBLASTOMA TREATMENT

Background: Cellular metabolism in glioblastoma multiforme, the most c ommon primary brain tumor in humans, is characterized by a high rate o f aerobic glycolysis that is dependent on mitochondria-bound hexokinas e. Moreover, high levels of glucose utilization and tumor aggressivene ss in glioblastoma are associated with a high density of mitochondrial benzodiazepine receptors, We sought to inhibit glioblastoma metabolis m by simultaneously inhibiting hexokinase with lonidamine and binding benzodiazepine receptors with diazepam, Methods: Cellular glioblastoma metabolism in five glioblastoma cell lines was assessed in vitro by m easuring cell proliferation (bg use of a tetrazolium-based colorimetri c assay, measurement of DNA synthesis, and assessment of tell cycle di stribution), by measuring membrane fluidity (by fluorescence polarizat ion measurement of cells stained with a fluorescent probe), and by mea suring changes in intracellular pH, Immunodeficient nude mice bearing subcutaneous xenografts of human glioblastoma cells mere used to asses s the antitumor activities of lonidamine and diazepam; the mice were t reated twice daily with lonidamine (total daily dose of 160 mg/kg body weight) and/or diazepam (total daily dose of 1 mg/kg body weight) for 10 consecutive days. Results: When used in combination, the two drugs had a stronger effect on glioblastoma cell proliferation and metaboli sm in vitro than did either agent used alone. In vivo, the combination of lonidamine and diazepam was significantly more effective in reduci ng glioblastoma tumor growth than either drug alone (two-sided P<.01, Mann-Whitney U test, comparing growth of treated tumors with that of u ntreated tumors); this tumor growth retardation was maintained as long as treatment was given. Conclusion: The combination of lonidamine and diazepam-drugs that target two distinct mitochondrial sites involved in cellular energy metabolism-potentiates the effects of the individua l drugs and mag prove useful in the treatment of human glioblastomas.