title: Inhibitors of XIAP sensitize CD40-activated chronic lymphocytic leukemia cells to CD95-mediated apoptosis.
abstract: Patients with chronic lymphocytic leukemia (CLL) treated with adenovirus CD154 (Ad-CD154, CD40 ligand [CD40L]) gene therapy experienced rapid reductions in leukemia cell counts and lymph node size associated with the induced expression of Fas (CD95). However, CLL cells initially resist CD95-mediated apoptosis within the first 3 days after CD40 ligation in vitro. Thereafter, they become sensitive, which is associated with the CD40-induced expression of the proapoptotic protein B-cell leukemia 2 homology 3 (BH3) interacting domain death agonist (Bid). We hypothesized that the initial resistance to CD95-mediated apoptosis may be due to the high-level expression of X-linked inhibitor of apoptosis protein (XIAP) by CLL cells. Consistent with this, CLL cells from patients 1 day after treatment with autologous Ad-CD154-transduced CLL cells became sensitive to CD95-mediated apoptosis following treatment with a novel XIAP inhibitor, 1540-14. Similarly, 1540-14 specifically enhanced CD95-mediated apoptosis of CLL cells following CD40 ligation in vitro. Immunoblot analyses demonstrated that treatment with 1540-14 allowed CD40-stimulated CLL cells to experience high-level activation of caspases-8 and -3 and cleavage of poly(adenosine diphosphate [ADP]-ribose) polymerase following CD95 ligation. This study demonstrates that distal apoptosis regulators contribute to the initial resistance of CD40-activated CLL cells to CD95-mediated apoptosis and suggests that XIAP inhibitors might enhance the effectiveness of immune-based treatment strategies that target CD40, such as CD154 gene therapy.
authors.affiliation: Moores Cancer Center at the University of California, San Diego, School of Medicine, University of California, San Diego, CA 92093, USA.
authors.forename: Arnon P
authors.initials: AP
authors.lastname: Kater
authors.forename: Frank
authors.initials: F
authors.lastname: Dicker
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangiola
authors.forename: Kate
authors.initials: K
authors.lastname: Welsh
authors.forename: Richard
authors.initials: R
authors.lastname: Houghten
authors.forename: John
authors.initials: J
authors.lastname: Ostresh
authors.forename: Adel
authors.initials: A
authors.lastname: Nefzi
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Clemencia
authors.initials: C
authors.lastname: Pinilla
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology* / Q000494:pharmacology; D020169:Caspases / Q000187:drug effects / Q000276:immunology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000276:immunology*; D008968:Molecular Conformation; D008970:Molecular Weight; D010671:Phenylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor / Q000276:immunology*
chemical_list: C504131:1396-34 compound; C504130:1540-14 compound; D000972:Antineoplastic Agents, Phytogenic; D019013:CD40 Antigens; D010671:Phenylurea Compounds; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor; D020169:Caspases