Figure 9.

Schematic representation of the effect of VAS3947 on AML cell lines. In AML cell lines, beside its effect as an inhibitor of NOX-derived ROS production (1), VAS3947 has other off-target effects. VAS3947 induces NOX independent cytoplasmic ROS decrease (2) as well as mitochondrial ROS production (3) by a yet unclear mechanism. Moreover, it efficiently thiol alkylates cysteine residues of GSH, leading to its cellular depletion (4) and aggregates with intracellular proteins leading to endoplasmic reticulum (ER) stress (5). The latter causes accumulation of proteins in the ER lumen, thus triggering the UPR activation via the phosphorylation and dimerization of PERK and IRE1α (6). This leads to the activation of eIF2α, JNK1, and P38MAPK, through their phosphorylation, and results in apoptosis via the cleavage of caspases, such as caspase 9, and consequently PARP (7).