Clotrimazole and bifonazole detach hexokinase from mitochondria of melanoma cells
Clotrimazole and bifonazole detach hexokinase from mitochondria of melanoma cells
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DOI：
10.1016/s0014-2999(97)01507-0
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发表时间：
1998-01-19
影响因子：
5
通讯作者：
Beitner, R
中科院分区：
文献类型：
--
作者：
Penso, J;Beitner, R
癌细胞的特征是糖酵解速率高。己糖激酶（ATP：D-己糖6-磷酸转移酶，EC 2.7.1.1）是唯一与线粒体结合的糖酵解酶，在癌细胞中异常高，并且被认为在调节细胞能量代谢和癌细胞生长速率中起关键作用。我们以前已经发现，克霉唑（1-（α-2-氯三苯甲基）咪唑）和联苯苄唑（1-（α-联苯-4-基苄基）咪唑），抗真菌唑类衍生物，最近被认为是钙调素拮抗剂，是钙调素拮抗剂，最有效地减少B16黑色素瘤细胞中的糖酵解和ATP水平。它们通过变构调节和糖酵解酶从细胞骨架上的分离发挥作用。在这里，我们报告了一个新的，额外的，这些药物的作用机制。我们发现，他们诱导剂量依赖性的脱离己糖激酶从B16黑色素瘤细胞的线粒体。这种效应先于细胞活力的降低。这些结果表明克霉唑和联苯苄唑可能是治疗黑色素瘤的有前途的药物。(C)1998年Elsevier Science B.V.
Cancer cells are characterized by a high rate of glycolysis. Hexokinase (ATP: D-hexose 6-phosphotransferase, EC 2.7.1.1), the only glycolytic enzyme which binds to mitochondria, is exceptionally high in cancer cells, and believed to play a key role in regulating cell energy metabolism and cancer cell growth rate. We have previously found that clotrimazole (1-(alpha-2-chlorotrityl)imidazole) and bifonazole (1-(alpha-biphenyl-4-ylbenzyl)imidazole), the antifungal azole derivatives, which were recently recognized as calmodulin antagonists, are calmodulin antagonists which most effectively reduce glycolysis and ATP level in B16 melanoma cells. They act through allosteric regulation and detachment of glycolytic enzymes from cytoskeleton. Here we report of a novel, additional, mechanism of action of these drugs. We show that they induce a dose-dependent detachment of hexokinase from mitochondria of B16 melanoma cells. This effect preceded the decrease in cell viability. These results suggest that clotrimazole and bifonazole may be promising drugs in treatment of melanoma. (C) 1998 Elsevier Science B.V.