PT  - JOURNAL ARTICLE
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
TI  - Voltage-Dependent Anion Channels Influence Cytotoxicity of ME-344, a Therapeutic Isoflavone
AID  - 10.1124/jpet.120.000009
DP  - 2020 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - JPET-AR-2020-000009
4099  - http://jpet.aspetjournals.org/content/early/2020/06/15/jpet.120.000009.short
4100  - http://jpet.aspetjournals.org/content/early/2020/06/15/jpet.120.000009.full
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 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.