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Calmodulin antagonists decrease glucose 1,6-bisphosphate, fructose 1,6-bisphosphate, ATP and viability of melanoma
L Glass-Marmor1, H Morgenstern, R Beitner
1Department of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.
Abstract:
Glycolysis is known to be the primary energy source in cancer cells. We investigated here the effect of four different calmodulin antagonists: thioridazine (10-[2-(1-methyl-2-piperidyl) ethyl]-2-methylthiophenothiazine), CGS 9343B (1,3-dihydro-1-[1-[(4-methyl-4H,6H-pyrrolo[1,2-a] [4,1]-benzoxazepin-4-yl)methyl]-4-piperidinyl]-2 H-benzimidazol-2-one (1:1) maleate), clotrimazole (1-(alpha-2-chlorotrityl)imidazole) and bifonazole (1-(alpha-biphenyl-4-ylbenzyl)imidazole), on the levels of glucose 1,6-bisphosphate and fructose 1,6-bisphosphate, the two stimulatory signal molecules of glycolysis, and on ATP content and cell viability in B16 melanoma cells. We found that all four substances significantly reduced the levels of glucose 1,6-bisphosphate, fructose 1,6-bisphosphate and ATP, in a dose- and time-dependent manner. Cell viability was reduced in a close correlation with the fall in ATP. The decrease in glucose 1,6-bisphosphate and fructose 1,6-bisphosphate did not result from the cytotoxic effects of the calmodulin antagonists, since their content was already reduced before any cytotoxic effect was observed. These findings suggest that the fall in the levels of the two signal molecules of glycolysis, induced by the calmodulin antagonists, causes a reduction in glycolysis and ATP levels, which eventually leads to cell death. Since cell proliferation was also reported to be inhibited by calmodulin antagonists, these substances are most promising agents in treatment of cancer by inhibiting both cell proliferation and the glycolytic supply of ATP required for cell growth.
Insights
Four calmodulin antagonists reduced key glycolysis molecules and ATP in B16 melanoma cells, leading to decreased cell viability. These findings highlight potential cancer treatments targeting both proliferation and energy production.
Area of Science:
- Biochemistry
- Cell Biology
- Cancer Research
Background:
- Glycolysis is a critical energy pathway for cancer cells.
- Calmodulin antagonists are being explored for therapeutic potential.
Purpose of the Study:
- To investigate the effects of four calmodulin antagonists on glycolysis in B16 melanoma cells.
- To assess the impact on key glycolytic intermediates, ATP levels, and cell viability.
Main Methods:
- Treatment of B16 melanoma cells with thioridazine, CGS 9343B, clotrimazole, and bifonazole.
- Measurement of glucose 1,6-bisphosphate, fructose 1,6-bisphosphate, and ATP levels.
- Assessment of cell viability.
Main Results:
- All four calmodulin antagonists significantly decreased glucose 1,6-bisphosphate, fructose 1,6-bisphosphate, and ATP levels.
- The reduction in these molecules occurred in a dose- and time-dependent manner.
- Decreased cell viability correlated with reduced ATP levels, preceding cytotoxic effects.
Conclusions:
- Calmodulin antagonists inhibit glycolysis by reducing key signal molecules, leading to ATP depletion and cell death.
- These compounds show promise for cancer treatment by targeting both cell proliferation and the glycolytic energy supply.