Small-Molecule XIAP Antagonist Restores Caspase-9-Mediated Apoptosis in XIAP-Positive Diffuse Large B-Cell Lymphoma Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 803-803 ◽  
Author(s):  
Saskia A.G.M. Cillessen ◽  
John C. Reed ◽  
Clemencia Pinilla ◽  
Chris J.L.M. Meijer ◽  
Erik Hooijberg ◽  
...  
Keyword(s):  
B Cell ◽  
Small Molecule ◽  
Mononuclear Cells ◽  
B Cell Lymphoma ◽  
Caspase 9 ◽  
Lymphoma Cells ◽  
Apoptosis Pathway ◽  
Expression Levels ◽  
Intrinsic Apoptosis Pathway ◽  
Large B Cell

Abstract Clinical outcome in patients with diffuse large B-cell lymphomas (DLBCL) is correlated with expression of inhibitors of the intrinsic apoptosis pathway, including XIAP. XIAP suppresses apoptosis through inhibiting active caspases-3, -7 and -9. In this study we investigated if the small-molecule XIAP antagonist 1396–12 induces cell death in cultured lymphoma cells of DLBCL patients and whether it is possible to predict whether a DLBCL will be sensitive to the XIAP antagonist. Treatment with this XIAP antagonist resulted 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 cases were characterized by high expression levels of XIAP and relatively low expression levels of Bcl-2. In addition, we found that XIAP antagonist sensitive lymphomas are characterized by constitutive caspase-9 activation and that the apoptosis inducing effect of the XIAP antagonist depends on this constitutive caspase 9 activity. These data indicate that the small-molecule XIAP antagonist can induce apoptosis in DLBCL cells by restoring caspase 9 mediated apoptosis 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 pre-defining patients most likely to benefit from XIAP antagonist therapy.

scholarly journals Small-molecule XIAP antagonist restores caspase-9–mediated apoptosis in XIAP-positive diffuse large B-cell lymphoma cells

Blood ◽  
2008 ◽  
Vol 111 (1) ◽  
pp. 369-375 ◽  
Author(s):  
Saskia A. G. M. Cillessen ◽  
John C. Reed ◽  
Kate Welsh ◽  
Clemencia Pinilla ◽  
Richard Houghten ◽  
...  
Keyword(s):  
B Cell ◽  
Small Molecule ◽  
Caspase 3 ◽  
B Cell Lymphoma ◽  
Caspase 9 ◽  
Lymphoma Cells ◽  
Apoptosis Pathway ◽  
Expression Levels ◽  
Apoptosis Protein ◽  
Large B Cell

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.

Polymorphisms in key regulator genes of the intrinsic apoptosis pathway in risk and clinical presentation of diffuse large B-cell lymphoma

2016 ◽  
Vol 35 (4) ◽  
pp. 911-913
Author(s):  
Angelo Borsarelli Carvalho Brito ◽  
Marcia Torresan Delamain ◽  
Cristiane de Oliveira ◽  
Carmino Antonio de Souza ◽  
José Vassallo ◽  
...  
Keyword(s):  
B Cell ◽  
Clinical Presentation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Large B Cell Lymphoma ◽  
Intrinsic Apoptosis Pathway ◽  
Regulator Genes ◽  
Large B Cell

scholarly journals MicroRNA-155 Downregulation Promotes Cell Cycle Arrest and Apoptosis in Diffuse Large B-Cell Lymphoma

2016 ◽  
Vol 24 (6) ◽  
pp. 415-427 ◽  
Author(s):  
Fu-qiang Zhu ◽  
Li Zeng ◽  
Na Tang ◽  
Ya-ping Tang ◽  
Bo-ping Zhou ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Formation ◽  
Lymphoma Cell ◽  
Lymphoma Cells ◽  
Expression Levels ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma in the adult population, and treatment of DLBCL is still unfavorable. Therefore, there is an urgent requirement to investigate the molecular mechanisms underlying DLBCL tumorigenesis. To study the potential function of microRNA-155 (miR-155) involved in the regulation of lymphoma, we monitored lymphoma cell behavior including proliferation, cell cycle, and apoptosis using CCK-8 and flow cytometry analysis. Real-time PCR was used to detect the expression levels of miR-155 in 118 lymphoma patients’ tissues, and Western blot was also used to analyze the expression level of proteins correlated with cell cycle and apoptosis in lymphoma cells. miR-155 expression levels were higher in lymphoma tissues compared with adjacent tissues. Downregulation of miR-155 inhibited lymphoma cell progress by arresting cell cycle in the G0/G1 phase and promoting apoptosis. Cell cycle-correlated proteins (cyclin B1, cyclin D1, and CDK4) were inhibited by downregulation of miR-155. Apoptosis-correlated proteins level (Bax/Bcl-2 and caspase 3 activity) were increased by downregulation of miR-155. In addition, a significant inverse correlation between the level of miR-155 and transforming growth factor-β receptor 2 (TGFBR2) was observed, which has been demonstrated to be a novel tumor suppressor gene. A further in vivo tumor formation study in nude mice indicated that downregulation of miR-155 in lymphoma cells delayed the progress of tumor formation. These findings indicate that miR-155 may serve as a useful potential target for the treatment of lymphoma.

scholarly journals IRONOMYCIN KILLS DIFFUSE LARGE B‐CELL LYMPHOMA CELLS BY TARGETING CELLULAR IRON HOMEOSTASIS

2021 ◽  
Vol 39 (S2) ◽  
Author(s):  
J. Devin ◽  
T. Cañeque ◽  
Y.‐L. Lin ◽  
L. Mondoulet ◽  
J.‐L. Veyrune ◽  
...  
Keyword(s):  
B Cell ◽  
Iron Homeostasis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cells ◽  
Cellular Iron ◽  
Large B Cell Lymphoma ◽  
Cellular Iron Homeostasis ◽  
Large B Cell

scholarly journals DNMT3A-2 EXPRESSION LEVELS CHARACTERISE DIFFUSE LARGE B-CELL LYMPHOMA WITH DISTINCT METHYLATION PATTERNS AND OUTCOME

2017 ◽  
Vol 35 ◽  
pp. 154-154
Author(s):  
A. Kuhnl ◽  
R. Shaikh ◽  
D. Cunningham ◽  
N. Counsell ◽  
S. Barrans ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Expression Levels ◽  
Large B Cell Lymphoma ◽  
Methylation Patterns ◽  
Large B Cell

scholarly journals Targeting mitochondrial respiration and the BCL2 family in MYC-associated B-cell lymphoma

2020 ◽  
Author(s):  
Giulio Donati ◽  
Micol Ravà ◽  
Marco Filipuzzi ◽  
Paola Nicoli ◽  
Laura Cassina ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
B Cell ◽  
Complex I ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Grade ◽  
Apoptosis Pathway ◽  
Bcl2 Family ◽  
Molecular Features ◽  
Intrinsic Apoptosis Pathway

AbstractMultiple molecular features, such as activation of specific oncogenes (e. g. MYC, BCL2) or a variety of gene expression signatures, have been associated with disease course in diffuse large B-cell lymphoma (DLBCL). Understanding the relationships between these features and their possible exploitation toward disease classification and therapy remains a major priority in the field. Here, we report that MYC activity in DLBCL is closely correlated with – and most likely a driver of – gene signatures related to Oxidative Phosphorylation (OxPhos). On this basis, we hypothesized that enzymes involved in Oxidative Phosphorylation, and in particular electron-transport chain (ETC) complexes, might constitute tractable therapeutic targets in MYC-associated lymphoma. Indeed, our data show that MYC sensitizes B-cells to IACS-010759, a selective inhibitor of ETC complex I. Mechanistically, IACS-010759 activates an ATF4-driven Integrated Stress Response (ISR), engaging the intrinsic apoptosis pathway through the transcription factor CHOP. In line with these findings, IACS-010759 shows synergy with the BCL2 inhibitor venetoclax against double-hit lymphoma (DHL), a high-grade form of DLBCL with concurrent activation of MYC and BCL2. Similarly, in BCL2-negative lymphoma cell lines, inhibition of the BCL2-related protein Mcl-1 potentiates killing by IACS-010759. Altogether, ETC complex I inhibition engages the ISR to lower the apoptotic threshold in MYC-driven lymphomas and, in combination with select BCL2-family inhibitors, provides a novel therapeutic principle against this aggressive DLBCL subset.Statement of significanceThis work points to OxPhos as a key MYC-activated process and a tractable therapeutic target toward personalized treatment of high-grade DLBCL, providing strong context-dependent cooperation with BH3-mimetic compounds.

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