Small molecule XIAP inhibitors sensitize childhood acute leukemia cells for apoptosis induction and break Bcl-2-mediated resistance

Children with high risk acute lymphoblastic leukemia (ALL) do not respond well to current treatments which is in part due to defects in apoptosis signaling, e.g. overexpression of “Inhibitor of Apoptosis Proteins“ (IAPs). This highlights the demand to develop novel strategies that counter apoptosis resistance. Here, we report that XIAP inhibitors and Smac mimetics sensitize acute leukemia cells for death receptor- and chemotherapy-induced apoptosis. Analysis of signaling pathways reveals that XIAP inhibitors enhance death receptor-triggered activation of caspases, loss of mitochondrial membrane potential and cyt…