Small molecule XIAP inhibitors sensitize childhood acute leukemia cells for CD95‐induced apoptosis

• Published in: International journal of cancer Vol. 126; no. 9; pp. 2216 - 2228
• Main Authors: Loeder, Sandra, Drensek, Annekathrin, Jeremias, Irmela, Debatin, Klaus‐Michael, Fulda, Simone
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.05.2010; Wiley-Blackwell
• Subjects: apoptosis; Apoptosis - drug effects; Biological and medical sciences; Caspases - metabolism; CD95; Cell Line, Tumor; Child; Fas Ligand Protein - physiology; fas Receptor - physiology; Hematologic and hematopoietic diseases; Humans; leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes - immunology; Medical sciences; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Tumors; X-Linked Inhibitor of Apoptosis Protein - antagonists & inhibitors; XIAP; Human; leukemia; CD95; Acute leukemia; XIAP; Malignant hemopathy; X linked inhibitor of apoptosis protein; Cancerology; Apoptosis inhibitory protein; Cell death; Fas Antigen; Inhibitor; Child; Cancer; Apoptosis
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24816

Escape of apoptosis may contribute to treatment failure in childhood acute lymphoblastic leukemia (ALL) calling for new approaches to overcome apoptosis resistance. Here, we provide for the first time evidence that small molecule inhibitors that target the anti‐apoptotic protein X‐linked inhibitor of apoptosis (XIAP) sensitize ALL cells for CD95‐induced apoptosis. XIAP inhibitors at subtoxic concentrations, but not a structurally related control compound, act synergistically with agonistic anti‐CD95 antibodies or MegaFasL, a hexameric form of CD95 ligand, to induce apoptosis in ALL cells. Further, XIAP inhibitors co‐operate with MegaFasL to reduce clonogenic survival of ALL cells demonstrating their effect also on long‐term survival. In contrast, XIAP inhibitors show little effect on MegaFasL‐mediated apoptosis in normal peripheral blood lymphocytes (PBLs), pointing to some tumor selectivity. Molecular studies reveal that XIAP inhibitors enhance CD95‐induced activation of caspases, loss of mitochondrial membrane potential and cytochrome c release in a caspase‐dependent manner. Importantly, XIAP inhibitors sensitize primary leukemic blasts from children with ALL for MegaFasL‐induced apoptosis. Thus, small molecule XIAP inhibitors present a promising novel approach to enhance CD95‐induced apoptosis in childhood acute leukemia.