Clotrimazole and bifonazole detach hexokinase from mitochondria of melanoma cells.
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.
Penso
J
J
Department of Life Sciences, Health Sciences Research Center, Bar-Ilan University, Ramat-Gan, Israel.
Beitner
R
R
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D003022:Clotrimazole / Q000494:pharmacology*; D006593:Hexokinase / Q000302:isolation & purification / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000648:ultrastructure; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D000890:Anti-Infective Agents; D000935:Antifungal Agents; D002147:Calmodulin; D007093:Imidazoles; D009363:Neoplasm Proteins; D006593:Hexokinase; D003022:Clotrimazole; C036596:bifonazole