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Erastin-Like Anti-Warburg Agents Prevent Mitochondrial Depolarization Induced by Free Tubulin and Decrease Lactate
David N DeHart1,2, John J Lemasters1,3, Eduardo N Maldonado1,2
11 Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA.
SLAS Discovery : Advancing Life Sciences R & D
|October 13, 2017
Summary
Researchers identified novel compounds that counteract the Warburg effect by targeting voltage-dependent anion channels (VDAC). These molecules restore mitochondrial function in cancer cells, offering a potential new therapeutic strategy.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Warburg metabolism in cancer involves suppressed mitochondrial activity, leading to increased aerobic glycolysis.
- Voltage-dependent anion channels (VDAC) regulate mitochondrial membrane potential (ΔΨ), crucial for cellular energy.
- Free tubulin in cancer cells inhibits VDAC, depolarizing mitochondria, while erastin counteracts this effect.
Purpose of the Study:
- To screen for novel compounds that inhibit the effect of tubulin on VDAC and restore mitochondrial membrane potential.
- To identify potential anti-Warburg drugs by targeting VDAC function.
Main Methods:
- Cell-based screening using HCC4006 cancer cells treated with nocodazole (NCZ) to induce tubulin aggregation.
- High-content imaging assessed mitochondrial membrane potential (ΔΨ) using Tetramethylrhodamine methylester (TMRM) fluorescence.
- Confocal microscopy validated lead compounds that antagonized NCZ-induced depolarization.
Main Results:
- Six lead compounds were identified that increased ΔΨ in the presence of NCZ, indicating VDAC channel opening.
- These compounds did not stabilize microtubules, suggesting their mechanism is independent of tubulin dynamics.
- The most potent compound reduced lactate production, a hallmark of Warburg metabolism.
Conclusions:
- Novel small molecules were discovered that target VDAC to counteract the Warburg effect.
- These compounds represent a potential new class of anti-cancer drugs by restoring mitochondrial function.
- The identified molecules offer a promising therapeutic avenue for cancers exhibiting Warburg metabolism.