© 1998 by Oxford University Press
Journal of the National Cancer Institute, Vol. 90, No. 18, 1400-1406,
September 16, 1998
©Copyright 1998 Oxford University Press
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Potentiation of Lonidamine and Diazepam, Two Agents Acting on Mitochondria, in Human Glioblastoma Treatment
Affiliations of authors: L. Miccoli, F. Poirson-Bichat, R. Bras Gonçalves, Y. Bourgeois, B. Dutrillaux, M.-F. Poupon, S. Oudard, Laboratoire de Cytogénétique Moléculaire et Oncologie, Institut Curie, Section de Recherche, Paris, France; F. Sureau, Laboratoire de Physico-Chimie Biomoléculaire et Cellulaire, Université Pierre et Marie Curie, Paris, France.
Correspondence to: Marie-France Poupon, M.D., Ph.D., UMR-147 CNRS, Institut Curie, Section de Recherche, 26, rue d'Ulm, 75248 Paris Cedex 05, France mfpoupon{at}curie.fr).
Abstract
Background: Cellular metabolism in glioblastoma multiforme, the most common primary brain tumor in humans, is characterized by a high rate of aerobic glycolysis that is dependent on mitochondria-bound hexokinase. Moreover, high levels of glucose utilization and tumor aggressiveness in glioblastoma are associated with a high density of mitochondrial benzodiazepine receptors. We sought to inhibit glioblastoma metabolism 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 measuring cell proliferation (by use of a tetrazolium-based colorimetric assay, measurement of DNA synthesis, and assessment of cell cycle distribution), by measuring membrane fluidity (by fluorescence polarization measurement of cells stained with a fluorescent probe), and by measuring changes in intracellular pH. Immunodeficient nude mice bearing subcutaneous xenografts of human glioblastoma cells were used to assess the antitumor activities of lonidamine and diazepam; the mice were treated 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 metabolism in vitro than did either agent used alone. In vivo, the combination of lonidamine and diazepam was significantly more effective in reducing glioblastoma tumor growth than either drug alone (two-sided P<.01, Mann–Whitney U test, comparing growth of treated tumors with that of untreated 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 individual drugs and may prove useful in the treatment of human glioblastomas. [J Natl Cancer Inst 1998;90:1400–6]
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