Premium
Small molecule XIAP inhibitors sensitize childhood acute leukemia cells for CD95‐induced apoptosis
Author(s) -
Loeder Sandra,
Drensek Annekathrin,
Jeremias Irmela,
Debatin KlausMichael,
Fulda Simone
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24816
Subject(s) - xiap , inhibitor of apoptosis , apoptosis , fas receptor , cancer research , caspase , leukemia , fas ligand , chemistry , immunology , biology , programmed cell death , microbiology and biotechnology , biochemistry
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.