Targeting IAP Proteins to Sensitize Childhood Acute Leukemia Cells for Apoptosis

XIAP, a member of „Inhibitor of Apoptosis“ (IAP) proteins, may present a suitable molecular target for therapeutic intervention, since it is expressed at high levels in acute leukemia and blocks apoptosis at a central point of the apoptotic machinery. Here, we report that neutralizing XIAP by small molecule inhibitors is a novel and effective approach to sensitize childhood acute leukemia cells for TRAIL-induced apoptosis. XIAP inhibitors at subtoxic concentrations synergize with TRAIL to induce apoptosis in acute lymphoblastic leukemia cells and to reduce clonogenic growth. Analysis of signaling pathways reveals that XIAP inhibitors enhance TRAIL-induced activation of caspases, loss of mitochondrial membrane potential and cytochrome c release in a caspase-dependent manner. Intriguingly, XIAP inhibitors overcome Bcl-2-mediated resistance to TRAIL by enhancing Bcl-2 cleavage and Bak conformational change. Thus, XIAP inhibitors combined with TRAIL even break Bcl-2-imposed resistance. Notably, XIAP inhibitors kill leukemic blasts from children with ALL ex vivo and cooperate with TRAIL to induce apoptosis. In contrast to malignant cells, XIAP inhibitors at equimolar concentrations alone or in combination with TRAIL are non-toxic to normal peripheral blood lymphocytes despite expression of the apoptosis-inducing TRAIL receptors on the cell surface. Most importantly, XIAP inhibitors significantly reduce leukemic burden in vivo in a mouse model of pediatric ALL engrafted in NOD/SCID mice. Thus, small molecule XIAP inhibitors present a promising novel approach for apoptosis-based therapy of childhood acute leukemia.