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.

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

Blood ◽

10.1182/blood.v110.11.803.803 ◽

2007 ◽

Vol 110 (11) ◽

pp. 803-803 ◽

Cited By ~ 2

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.

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Inhibition of the Intrinsic Apoptosis Pathway Downstream of Caspase-9 Activation Causes Chemotherapy Resistance in Diffuse Large B-Cell Lymphoma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-06-2891 ◽

2007 ◽

Vol 13 (23) ◽

pp. 7012-7021 ◽

Cited By ~ 17

Author(s):

Saskia A.G.M. Cillessen ◽

Corine J. Hess ◽

Erik Hooijberg ◽

Kitty C.M. Castricum ◽

Pim Kortman ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Chemotherapy Resistance ◽

B Cell Lymphoma ◽

Intrinsic Apoptosis ◽

Caspase 9 ◽

Apoptosis Pathway ◽

Large B Cell Lymphoma ◽

Intrinsic Apoptosis Pathway ◽

Large B Cell

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The regulation of miR-320a/XBP1 axis through LINC00963 for endoplasmic reticulum stress and autophagy in diffuse large B-cell lymphoma

10.21203/rs.3.rs-353877/v1 ◽

2021 ◽

Author(s):

Yuying Cui ◽

Hui Xu ◽

Yu Yang ◽

Dongmei Zhao ◽

Yu Wen ◽

...

Keyword(s):

B Cell ◽

Caspase 3 ◽

Cell Lymphoma ◽

Xenograft Model ◽

B Cell Lymphoma ◽

Growth Delay ◽

Apoptosis Pathway ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Introduction: Huge amounts of gene-sequencing data have been used to guide fundamental researches. The study combined bioinformatics tools with basic study to analyze the pathological mechanisms of diffuse large B-cell lymphoma. Methods: A LncRNA-miRNA-mRNA ceRNA network of diffuse large B cell lymphoma was constructed by GTEx combined with TCGA database analysis. qPCR was used to detect the expression of LINC00963 and miR-320a in DLBCL cell lines. The proteins levels of UPR sensors, GRP78, p-IRE1α, IRE1α, active ATF6, ATF4 and XBP1, were assessed through Western blot, along with apoptosis markers (Bcl-2, Bax, caspase 3) and autophagy indicators (Beclin1, LC3II, LC3I and p62) after LINC00963 overexpression or miR-320a overexpression in vitro. Additionally, the expression of LC3 was analyzed through immunofluorescence (IF) assay. Results: Evaluation of SUDHL4 cell showed marked up-regulation of key elements of the UPR (GRP78, p-IRE1α, spliced XBP-1(XBP-1(s))), apoptosis (Bax, cleaved caspase 3) and autophagy (Beclin1, LC3II) after LINC00963 overexpression in vitro, whereas miR-320a mimic reversed the effects. Besides, LINC00963 targeted miR-320a while miR-320a bound to the 3’UTR of XBP1. The work also found that LINC00963 overexpression resulted in significant tumor growth delay in a xenograft model of DLBCL. Conclusion: Mechanistically, LINC00963 / miR-320a regulated XBP1-apoptosis pathway and autophagy, making this pathway an attractive therapeutic target for selective targeting. The data presented here are the first to comprehensively survey the mechanism of LINC00963 / miR-320a/XBP1 in DLBCL.

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An orally available small molecule BCL6 inhibitor effectively suppresses diffuse large B cell lymphoma cells growth in vitro and in vivo

Cancer Letters ◽

10.1016/j.canlet.2021.12.035 ◽

2022 ◽

Author(s):

Yajing Xing ◽

Weikai Guo ◽

Min Wu ◽

Jiuqing Xie ◽

Dongxia Huang ◽

...

Keyword(s):

B Cell ◽

Small Molecule ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphoma Cells ◽

Large B Cell Lymphoma ◽

Large B Cell

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The regulation of miR-320a/XBP1 axis through LINC00963 for endoplasmic reticulum stress and autophagy in diffuse large B-cell lymphoma

Cancer Cell International ◽

10.1186/s12935-021-01992-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yuying Cui ◽

Hui Xu ◽

Yu Yang ◽

Dongmei Zhao ◽

Yu Wen ◽

...

Keyword(s):

B Cell ◽

Caspase 3 ◽

Therapeutic Potential ◽

Cell Lymphoma ◽

Xenograft Model ◽

B Cell Lymphoma ◽

Apoptosis Pathway ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Background This study incorporates fundamental research referring to considerable amounts of gene-sequencing data and bioinformatics tools to analyze the pathological mechanisms of diffuse large B-cell lymphoma (DLBCL). Methods A lncRNA-miRNA-mRNA ceRNA network of DLBCL was constructed through database analysis combining GTEx and TCGA. qPCR was used to detect the expression of LINC00963 and miR-320a in DLBCL cell lines. After LINC00963 or miR-320a overexpression in vitro, western blot was performed to assess the protein levels of UPR sensors (GRP78, p-IRE1, IRE1, active ATF6, ATF4 and XBP1), along with apoptosis markers (Bcl-2, Bax, caspase 3) and autophagy indicators (Beclin1, LC3II, LC3I and p62). Additionally, the expression of LC3 was analyzed through immunofluorescence (IF) assay. Results Following LINC00963 overexpression in vitro, SUDHL4 cell line showed a marked increase in the level of UPR-related GRP78, p-IRE1 and spliced XBP-1/XBP-1(s), apoptosis-related Bax and cleaved caspase 3, as well as autophagy-related Beclin1 and LC3II, whereas miR-320a mimic greatly diminished the effects of LINC00963 overexpression. Moreover, LINC00963 targeted miR-320a while miR-320a bound to the 3’UTR of XBP1. It was also found that LINC00963 overexpression resulted in significantly delayed tumor growth in a xenograft model of DLBCL. Conclusion Mechanistically, LINC00963/miR-320a regulated XBP1-apoptosis pathway and autophagy, implying the therapeutic potential of this pathway for selective targeting. The data presented here illustrated the mechanism of LINC00963/miR-320a/XBP1 in DLBCL for the first time.

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

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504016x14685034103473 ◽

2016 ◽

Vol 24 (6) ◽

pp. 415-427 ◽

Cited By ~ 20

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.

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Anticancer Activity of Platinum (II) Complex with 2-Benzoylpyridine by Induction of DNA Damage, S-Phase Arrest, and Apoptosis

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666191112114340 ◽

2020 ◽

Vol 20 (4) ◽

pp. 504-517

Author(s):

Yu-Lan Li ◽

Xin-Li Gan ◽

Rong-Ping Zhu ◽

Xuehong Wang ◽

Duan-Fang Liao ◽

...

Keyword(s):

Dna Damage ◽

B Cell ◽

Anticancer Activity ◽

Cancer Cells ◽

Hepg2 Cells ◽

Caspase 3 ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

S Phase ◽

Caspase 9

Objective: To overcome the disadvantages of cisplatin, numerous platinum (Pt) complexes have been prepared. However, the anticancer activity and mechanism of Pt(II) complexed with 2-benzoylpyridine [Pt(II)- Bpy]: [PtCl2(DMSO)L] (DMSO = dimethyl sulfoxide, L = 2-benzoylpyridine) in cancer cells remain unknown. Methods: Pt(II)-Bpy was synthesized and characterized by spectrum analysis. Its anticancer activity and underlying mechanisms were demonstrated at the cellular, molecular, and in vivo levels. Results: Pt(II)-Bpy inhibited tumor cell growth, especially HepG2 human liver cancer cells, with a halfmaximal inhibitory concentration of 9.8±0.5μM, but with low toxicity in HL-7702 normal liver cells. Pt(II)- Bpy induced DNA damage, which was demonstrated through a marked increase in the expression of cleavedpoly (ADP ribose) polymerase (PARP) and gamma-H2A histone family member X and a decrease in PARP expression. The interaction of Pt(II)-Bpy with DNA at the molecular level was most likely through an intercalation mechanism, which might be evidence of DNA damage. Pt(II)-Bpy initiated cell cycle arrest at the S phase in HepG2 cells. It also caused severe loss of the mitochondrial membrane potential; a decrease in the expression of caspase-9 and caspase-3; an increase in reactive oxygen species levels; the release of cytochrome c and apoptotic protease activation factor; and the activation of caspase-9 and caspase-3 in HepG2 cells, which in turn resulted in apoptosis. Meanwhile, changes in p53 and related proteins were observed including the upregulation of p53, the phosphorylation of p53, p21, B-cell lymphoma-2-associated X protein, and NOXA; and the downregulation of B-cell lymphoma 2. Moreover, Pt(II)-Bpy displayed marked inhibitory effects on tumor growth in the HepG2 nude mouse model. Conclusion: Pt(II)-Bpy is a potential candidate for cancer chemotherapy.

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