TY - JOUR 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 DO - 10.1124/jpet.120.000009 SP - JPET-AR-2020-000009 AU - Leilei Zhang AU - Danyelle Townsend AU - Morgan Morris AU - Eduardo N. Maldonado AU - Yu-Lin Jiang AU - Ann-Marie Broome AU - Jennifer R. Bethard AU - Lauren E. Ball AU - Kenneth D. Tew Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/06/15/jpet.120.000009.abstract N2 - 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 1 and 2 (VDAC1, 2) were identified as drug targets. To determine the importance of VDAC1 or 2 to cytotoxicity we used lung cancer cells either sensitive (H460) or intrinsically resistant (H596) to the drug. In H460 cells, depletion of VDAC1 and VDAC2 by siRNA impacted ME-344 effects by: diminishing generation of reactive oxygen species (ROS); preventing mitochondrial membrane potential (ΔΨm) dissipation; 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. ER -