Small molecule XIAP inhibitors cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells and overcome Bcl-2–mediated resistance

RIP1 Protein-dependent Assembly of a Cytosolic Cell Death Complex Is Required for Inhibitor of Apoptosis (IAP) Inhibitor-mediated Sensitization to Lexatumumab-induced Apoptosis

“…The concept of simultaneously targeting IAP proteins and TRAIL receptors is, in principle, suitable for clinical translation because IAP antagonists and anti-TRAIL receptor antibodies have individually already entered the stage of early clinical evaluation (33,34). In addition, we previously reported that IAP inhibitors preferentially prime various cancer types, but not non-malignant cells, to TRAIL receptor-induced apoptosis, pointing to some cancer selectivity (35)(36)(37). Thus, by demonstrating that IAP inhibitors and lexatumumab synergistically trigger apoptosis in a RIP1-dependent and TNF␣-independent manner in RMS cells, our findings have important implications for the development of experimental treatment strategies for RMS.…”

“…Thus, by demonstrating that IAP inhibitors and lexatumumab synergistically trigger apoptosis in a RIP1-dependent and TNF␣-independent manner in RMS cells, our findings have important implications for the development of experimental treatment strategies for RMS. Beyond RMS, this study, together with our previous reports (18,(35)(36)(37)(38), underscores the broader relevance of the concept of simultaneously targeting IAP proteins and TRAIL receptors as a promising anticancer strategy.…”

Exploiting inhibitor of apoptosis proteins as therapeutic targets in hematological malignancies

“…89 In childhood ALL, IAP antagonists at subtoxic concentrations acted in concert with TRAIL to trigger apoptosis in a synergistic manner. 90 In contrast, a structurally related control compound did not synergize with TRAIL, underlining the specificity of the sensitizing effect provided by the IAP antagonists. 90 In addition, the IAP antagonist cooperated with TRAIL to suppress colony formation of ALL cells, 90 demonstrating an effect also on longterm clonogenic survival.…”

“…90 In contrast, a structurally related control compound did not synergize with TRAIL, underlining the specificity of the sensitizing effect provided by the IAP antagonists. 90 In addition, the IAP antagonist cooperated with TRAIL to suppress colony formation of ALL cells, 90 demonstrating an effect also on longterm clonogenic survival. Notably, IAP antagonists even bypassed Bcl-2-conferred resistance to TRAIL-induced apoptosis by switching type II leukemia cells, which depend on mitochondrial signaling for full activation of effector caspases, into type I cells that signal to TRAIL-induced caspase activation and apoptosis, independently of high Bcl-2 levels.…”

PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis

“…In the left panel, Bax activation was analyzed by immunoprecipitation of protein lysates using the active conformation-specific anti-Bax antibody 6A7 as previously described (Hacker et al, 2009) and Bax expression was analyzed by western blotting. In the right panel, Bak activation was analyzed at 12 h by flow cytometry using an active conformation-specific anti-Bak antibody as previously described (Fakler et al, 2009 Targeting PI3K in neuroblastoma A Bender et al Figure 2 PI3K inhibitors shift the balance towards pro-apoptotic Bcl-2 proteins and cooperate with Doxorubicin to trigger p53-dependent apoptosis. (a, b) SH-EP cells were stably transduced with a vector containing short hairpin RNA (shRNA) against Mcl-1 (a), Noxa (a), p53 (b) or control shRNA using pRETRO-SUPER vector as previously described (Vogler et al, 2007) and shRNA targeting Mcl-1 (Ammann et al, 2009), Noxa (Alves et al, 2006), p53 (Brummelkamp et al, 2002) or a sequence with no corresponding part in the human genome (Vogler et al, 2007).…”