TY - JOUR
T1 - Small-molecule XIAP antagonist restores caspase-9-mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells
AU - Cillessen, Saskia A.G.M.
AU - Reed, John C.
AU - Welsh, Kate
AU - Pinilla, Clemencia
AU - Houghten, Richard
AU - Hooijberg, Erik
AU - Deurhof, José
AU - Castricum, Kitty C.M.
AU - Kortman, Pim
AU - Hess, Corine J.
AU - Ossenkoppele, Gert J.
AU - Meijer, Chris J.L.M.
AU - Oudejans, Joost J.
PY - 2008/1/1
Y1 - 2008/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=38049160750&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38049160750&partnerID=8YFLogxK
U2 - 10.1182/blood-2007-04-085480
DO - 10.1182/blood-2007-04-085480
M3 - Article
C2 - 17916749
AN - SCOPUS:38049160750
SN - 0006-4971
VL - 111
SP - 369
EP - 375
JO - Blood
JF - Blood
IS - 1
ER -