Potentiation of lonidamine and diazepam, two agents acting on mitochondria, in human glioblastoma treatment
Potentiation of lonidamine and diazepam, two agents acting on mitochondria, in human glioblastoma treatment
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DOI：
10.1093/jnci/90.18.1400
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发表时间：
1998-09-16
期刊：
影响因子：
--
通讯作者：
Oudard, S
中科院分区：
文献类型：
--
作者：
Miccoli, L;Poirson-Bichat, F;Oudard, S
背景资料：多形性胶质母细胞瘤是人类最常见的原发性脑肿瘤，其细胞代谢的特征在于依赖于与α-己糖激酶结合的高速率有氧糖酵解。此外，胶质母细胞瘤中高水平的葡萄糖利用和肿瘤侵袭性与高密度的线粒体苯二氮卓受体相关。我们试图通过同时用氯尼达明抑制己糖激酶和用地西泮结合苯二氮卓受体来抑制胶质母细胞瘤代谢。通过测量细胞增殖来评估五种胶质母细胞瘤细胞系的细胞胶质母细胞瘤代谢（例如使用基于四唑的比色测定、测量DNA合成和评估Tell循环分布），通过测量膜流动性（通过用荧光探针染色的细胞的荧光偏振测量），并通过测量细胞内pH值的变化，免疫缺陷裸鼠皮下移植人胶质母细胞瘤细胞，用于评价氯尼达明和地西泮的抗肿瘤活性;用氯尼达明（每日总剂量为160 mg/kg体重）和/或地西泮（每日总剂量为1 mg/kg体重）每天两次连续10天处理小鼠。结果如下：当联合使用时，这两种药物在体外对胶质母细胞瘤细胞增殖和代谢的作用比单独使用任何一种药物都强。在体内，氯尼达明和地西泮联合用药在减少胶质母细胞瘤肿瘤生长方面比单独使用任何一种药物都更有效（双侧P
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 (bg use of a tetrazolium-based colorimetric assay, measurement of DNA synthesis, and assessment of tell 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 mere 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