Opening of Voltage Dependent Anion Channels Promotes Reactive Oxygen Species Generation, Mitochondrial Dysfunction and Cell Death in Cancer Cells.

Opening of Voltage Dependent Anion Channels Promotes Reactive Oxygen Species Generation, Mitochondrial Dysfunction and Cell Death in Cancer Cells. Biochem Pharmacol. 2017 Dec 28;: Authors: DeHart DN, Fang D, Heslop K, Li L, Lemasters JJ, Maldonado EN Abstract Enhancement of aerobic glycolysis and suppression of mitochondrial metabolism characterize the pro-proliferative Warburg phenotype of cancer cells. High free tubulin in cancer cells closes voltage dependent anion channels (VDAC) to decrease mitochondrial membrane potential (ΔΨ), an effect antagonized by erastin, the canonical promotor of ferroptosis. Previously, we identified six compounds (X1-X6) that also block tubulin-dependent mitochondrial depolarization. Here, we hypothesized that VDAC opening after erastin and X1-X6 increases mitochondrial metabolism and reactive oxygen species (ROS) formation, leading to ROS-dependent mitochondrial dysfunction, bioenergetic failure and cell death. Accordingly, we characterized erastin and the two most potent structurally unrelated lead compounds, X1 and X4, on ROS formation, mitochondrial function and cell viability. Erastin, X1 and X4 increased ΔΨ followed closely by an increase of mitochondrial ROS generation within 30 to 60 min. Subsequently, mitochondria began to depolarize after an hour or longer indicative of mitochondrial dysfunction. N-acetylcysteine (NAC, glutathione precursor and ROS scavenger) and MitoQ (mitochondrially ta...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research