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

• Published in: Blood Vol. 113; no. 8; pp. 1710 - 1722
• Main Authors: Fakler, Melanie, Loeder, Sandra, Vogler, Meike, Schneider, Katja, Jeremias, Irmela, Debatin, Klaus-Michael, Fulda, Simone
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 19.02.2009; Americain Society of Hematology
• Subjects: Animals; Antineoplastic agents; Apoptosis - physiology; Biological and medical sciences; Caspases - metabolism; Cell Survival - physiology; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Synergism; fas Receptor - metabolism; General aspects; Hematologic and hematopoietic diseases; Humans; Jurkat Cells; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Mitochondria - physiology; Peptide Fragments - genetics; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA, Small Interfering - pharmacology; TNF-Related Apoptosis-Inducing Ligand - metabolism; TNF-Related Apoptosis-Inducing Ligand - pharmacology; X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors; X-Linked Inhibitor of Apoptosis Protein - genetics; Xenograft Model Antitumor Assays; Human; Antineoplastic agent; Treatment resistance; Rodentia; XIAP protein; Malignant hemopathy; Vertebrata; Mammalia; Treatment; Apoptosis inhibitory protein; Mouse; Cell death; Lymphoproliferative syndrome; Animal; C-Onc gene; Genetics; TNF related apoptosis inducing ligand; Acute lymphocytic leukemia; Child; Protooncogene; Cancer; Apoptosis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-09-114314

Defects in apoptosis contribute to poor outcome in pediatric acute lymphoblastic leukemia (ALL), calling for novel strategies that counter apoptosis resistance. Here, we demonstrate for the first time that small molecule inhibitors of the antiapoptotic protein XIAP cooperate with TRAIL to induce apoptosis in childhood acute leukemia cells. XIAP inhibitors at subtoxic concentrations, but not a structurally related control compound, synergize with TRAIL to trigger apoptosis and to inhibit clonogenic survival of acute leukemia cells, whereas they do not affect viability of normal peripheral blood lymphocytes, suggesting some tumor selectivity. 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, indicating that they promote a caspase-dependent feedback mitochondrial amplification loop. Of note, XIAP inhibitors even overcome Bcl-2–mediated resistance to TRAIL by enhancing Bcl-2 cleavage and Bak conformational change. Importantly, XIAP inhibitors kill leukemic blasts from children with ALL ex vivo and cooperate with TRAIL to induce apoptosis. In vivo, they significantly reduce leukemic burden in a mouse model of pediatric ALL engrafted in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. Thus, XIAP inhibitors present a promising novel approach for apoptosis-based therapy of childhood ALL.