Small-molecule XIAP antagonist restores caspase-9 mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells.
Clinical outcome in patients with primary nodal diffuse large B-cell lymphomas (DLBCLs) is correlated with expression of inhibitors of the intrinsic apoptosis pathway, including X-linked inhibitor of apoptosis protein (XIAP). XIAP suppresses apoptosis through inhibiting active caspase-3, caspase-7, and caspase-9. In this study, we investigated to see if the small-molecule XIAP antagonist 1396-12 induces cell death in cultured lymphoma cells of patients with DLBCL. Treatment with this XIAP antagonist resulted in relief of caspase-3 inhibition and in induction of apoptosis in 16 of 20 tested DLBCL samples. Sensitivity to the XIAP antagonist was observed in both chemotherapy-refractory and -responsive DLBCL, but did not affect peripheral blood mononuclear cells and tonsil germinal-center B cells from healthy donors. XIAP antagonist-sensitive samples were characterized by high expression levels of XIAP, relatively low expression levels of Bcl-2, and by constitutive caspase-9 activation. These data indicate that the small-molecule XIAP antagonist can induce apoptosis in cultured DLBCL cells and therefore should be considered for possible development as a therapy for these patients. In vitro sensitivity to the XIAP antagonist can be predicted based on biological markers, suggesting the possibility of predefining patients most likely to benefit from XIAP antagonist therapy.
Cillessen
Saskia A G M
SA
Department of Clinical Pathology, VU University Medical Center, Amsterdam, the Netherlands.
Reed
John C
JC
Welsh
Kate
K
Pinilla
Clemencia
C
Houghten
Richard
R
Hooijberg
Erik
E
Deurhof
José
J
Castricum
Kitty C M
KC
Kortman
Pim
P
Hess
Corine J
CJ
Ossenkoppele
Gert J
GJ
Meijer
Chris J L M
CJ
Oudejans
Joost J
JJ
D000814:Aniline Compounds / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D014066:Palatine Tonsil / Q000166:cytology; D010671:Phenylurea Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000814:Aniline Compounds; D000972:Antineoplastic Agents, Phytogenic; C500895:N-(6-((anilinocarbonyl)amino)-5-((anilinocarbonyl)((1-(4-cyclohexylbutyl)pyrrolidin-2-yl)methyl)amino)hexyl)-N-methyl-N'-phenylurea; D010671:Phenylurea Compounds; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D005047:Etoposide; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9