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Voltage-Dependent Anion Channels Influence Cytotoxicity of ME-344, a Therapeutic Isoflavone
- Source :
- The Journal of Pharmacology and Experimental Therapeutics
- Publication Year :
- 2020
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2020.
-
Abstract
- ME-344 is a second-generation cytotoxic isoflavone with anticancer activity promulgated through interference with mitochondrial functions. Using a click chemistry version of the drug together with affinity-enriched mass spectrometry, voltage-dependent anion channels (VDACs) 1 and 2 were identified as drug targets. To determine the importance of VDAC1 or 2 to cytotoxicity, we used lung cancer cells that were either sensitive (H460) or intrinsically resistant (H596) to the drug. In H460 cells, depletion of VDAC1 and VDAC2 by small interfering RNA impacted ME-344 effects by diminishing generation of reactive oxygen species (ROS), preventing mitochondrial membrane potential dissipation, and moderating ME-344-induced cytotoxicity and mitochondrial-mediated apoptosis. Mechanistically, VDAC1 and VDAC2 knockdown prevented ME-344-induced apoptosis by inhibiting Bax mitochondrial translocation and cytochrome c release as well as apoptosis in these H460 cells. We conclude that VDAC1 and 2, as mediators of the response to oxidative stress, have roles in modulating ROS generation, Bax translocation, and cytochrome c release during mitochondrial-mediated apoptosis caused by ME-344. SIGNIFICANCE STATEMENT: Dissecting preclinical drug mechanisms are of significance in development of a drug toward eventual Food and Drug Administration approval.
- Subjects :
- 0301 basic medicine
Small interfering RNA
Voltage-dependent anion channel
Antineoplastic Agents
Apoptosis
03 medical and health sciences
Neuropharmacology
0302 clinical medicine
Cell Line, Tumor
Humans
Cytotoxicity
bcl-2-Associated X Protein
Membrane Potential, Mitochondrial
Pharmacology
chemistry.chemical_classification
Reactive oxygen species
biology
Voltage-Dependent Anion Channel 2
Voltage-Dependent Anion Channel 1
Cytochrome c
Isoflavones
Cell biology
030104 developmental biology
chemistry
biology.protein
Molecular Medicine
Reactive Oxygen Species
VDAC2
VDAC1
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15210103 and 00223565
- Volume :
- 374
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacology and Experimental Therapeutics
- Accession number :
- edsair.doi.dedup.....221dc24fe663781c9c0b01b4d356d204