期刊
SLAS DISCOVERY
卷 23, 期 1, 页码 23-33出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/2472555217731556
关键词
erastin; mitochondrial membrane potential; tubulin; voltage-dependent anion channel; Warburg metabolism
资金
- COBRE Pilot Project [GM103542]
- [4R25GM072643-12]
- [T32DK083262]
- [R01 DK073336]
- [R01 DK037034]
- [14.Z50.31.0028]
- [R01 CA18445601]
- [P50 CA058187]
- [ACS 13-043-01]
- [P30 CA138313]
In Warburg metabolism, suppression of mitochondrial metabolism contributes to a low cytosolic ATP/ADP ratio favoring enhanced aerobic glycolysis. Flux of metabolites across the mitochondrial outer membrane occurs through voltage-dependent anion channels (VDAC). In cancer cells, free dimeric tubulin induces VDAC closure and dynamically regulates mitochondrial membrane potential (Delta Psi). Erastin, a small molecule that binds to VDAC, antagonizes the inhibitory effect of tubulin on VDAC and hyperpolarizes mitochondria in intact cells. Here, our aim was to identify novel compounds from the ChemBridge DIVERSet library that block the inhibitory effect of tubulin on Delta Psi using cell-based screening. HCC4006 cells were treated with nocodazole (NCZ) to increase free tubulin and decrease Delta Psi in the presence or absence of library compounds. Tetramethylrhodamine methylester (TMRM) fluorescence was assessed by high-content imaging to determine changes in Delta Psi. Compounds were considered positive if Delta Psi increased in the presence of NCZ. Using confocal microscopy, we identified and validated six lead molecules that antagonized the depolarizing effect of NCZ. Lead compounds and erastin did not promote microtubule stabilization, so changes in Delta Psi were independent of tubulin dynamics. The most potent lead compound also decreased lactate formation. These novel small molecules represent a potential new class of anti-Warburg drugs.
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