RT Journal Article
SR Electronic
T1 Voltage-Dependent Anion Channels Influence Cytotoxicity of ME-344, a Therapeutic Isoflavone
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 308
OP 318
DO 10.1124/jpet.120.000009
VO 374
IS 2
A1 Leilei Zhang
A1 Danyelle M. Townsend
A1 Morgan Morris
A1 Eduardo N. Maldonado
A1 Yu-Lin Jiang
A1 Ann-Marie Broome
A1 Jennifer R. Bethard
A1 Lauren E. Ball
A1 Kenneth D. Tew
YR 2020
UL http://jpet.aspetjournals.org/content/374/2/308.abstract
AB 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.