Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that affect tumor growth and survival, including inhibition of cell cycle progression, induction of tumor cell-selective apoptosis, suppression of angiogenesis, and modulation of immune responses, and show promising activity against hematological malignancies in clinical trials. Using the Emu-myc model of B cell lymphoma, we screened tumors with defined genetic alterations in apoptotic pathways for therapeutic responsiveness to the HDACi vorinostat. We demonstrated a direct correlation between induction of tumor cell apoptosis in vivo and therapeutic efficacy. Vorinostat did not require p53 activity or a functional death receptor pathway to kill Emu-myc lymphomas and mediate a therapeutic response but depended on activation of the intrinsic apoptotic pathway with the proapoptotic BH3-only proteins Bid and Bim playing an important role. Our studies provide important information regarding the mechanisms of action of HDACi that have broad implications regarding stratification of patients receiving HDACi therapy alone or in combination with other anticancer agents.
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PMID:Analysis of the apoptotic and therapeutic activities of histone deacetylase inhibitors by using a mouse model of B cell lymphoma. 1747 Jul 84

B-cell lymphoma-2 (Bcl-2) family members have been demonstrated to play a crucial role in the regulation of apoptosis as mediators in between the apical stimuli sensing steps and the executory mechanisms of apoptosis. Deregulation of their role may subvert the homeostasis of a given tissue and collaborate in the genesis of a myriad of diseases characterised by exacerbated or insufficient apoptosis, including diseases such as neurodegenerative diseases or cancer. Structural studies have defined homology regions shared by the members of the family that are responsible of the network of interactions established amongst the members of the family. These proteins usually form heterodimers between the so called antiapoptotic multidomain members and the proapoptotic BH3-only proteins. As a consequence, mitochondrial apoptogenic proteins are released to the cytoplasm and the apoptotic signal proceeds towards the final, execution phase of the apoptotic process. The high complexity of the family (more than 20 members have been isolated) makes the study of individual proteins difficult. Genetic approaches have revealed a high degree of redundancy in the family. Only a few proteins belonging to the antiapoptotic group have been proven to be essential for correct embryonic development. Genetic inactivation in mice shows a dramatic phenotype characterised by massive cell death in multiple tissues during embryogenesis, which leads from very early up to perinatal death. This genetic evidence proves the importance of the members of the family for the regulation of apoptosis in order to achieve the proper development and homeostasis of tissues and organs.
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PMID:Role of Bcl-2 family members on apoptosis: what we have learned from knock-out mice. 1748 8

The grouper iridovirus (GIV) belongs to the family Iridoviridae, whose genome contains an antiapoptotic B-cell lymphoma (Bcl)-2-like gene. This study was carried-out to understand whether GIV blocks apoptosis in its host. UV-irradiated grouper kidney (GK) cells underwent apoptosis. However, a DNA fragmentation assay of UV-exposed GK cells after GIV infection revealed an inhibition of apoptosis. The UV- or heat-inactivated GIV failed to inhibit apoptosis, implying that a gene or protein of the viral particle might contribute to an apoptosis inhibitory function. The DNA ladder assay for GIV-infected GK cells after UV irradiation confirmed that apoptosis inhibition was an early process which occurred as early as 5 min post-infection. A GIV-Bcl sequence comparison showed distant sequence similarities to that of human and four viruses; however, all possessed the putative Bcl-2 homology (BH) domains of BH1, BH2, BH3, and BH4, as well as a transmembrane domain. Northern blot hybridization showed that GIV-Bcl transcription began at 2 h post-infection, and the mRNA level significantly increased in the presence of cycloheximide or aphidicolin, indicating that this GIV-Bcl is an immediate-early gene. This was consistent with the Western blot results, which also revealed that the virion carries the Bcl protein. We observed the localization of GIV-Bcl on the mitochondrial membrane and other defined intracellular areas. By immunostaining, it was proven that GIV-Bcl-expressing cells effectively inhibited apoptosis. Taken together, these results demonstrate that GIV inhibits the promotion of apoptosis by GK cells, which is mediated by the immediate early expressed viral Bcl gene.
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PMID:Iridovirus Bcl-2 protein inhibits apoptosis in the early stage of viral infection. 1795 72

B cell lymphoma 2 (Bcl-2) homology domain 3 (BH3)-only proteins of the Bcl-2 family are important functional adaptors that link cell death signals to the activation of Bax and/or Bak. The BH3-only protein Nbk/Bik induces cell death via an entirely Bax-dependent/Bak-independent mechanism. In contrast, cell death induced by the short splice variant of Bcl-x depends on Bak but not Bax. This indicates that Bak is functional but fails to become activated by Nbk. Here, we show that binding of myeloid cell leukemia 1 (Mcl-1) to Bak persists after Nbk expression and inhibits Nbk-induced apoptosis in Bax-deficient cells. In contrast, the BH3-only protein Puma disrupts Mcl-1-Bak interaction and triggers cell death via both Bax and Bak. Targeted knockdown of Mcl-1 overcomes inhibition of Bak and allows for Bak activation by Nbk. Thus, Nbk is held in check by Mcl-1 that interferes with activation of Bak. The finding that different BH3-only proteins rely specifically on Bax, Bak, or both has important implications for the design of anticancer drugs targeting Bcl-2.
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PMID:Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis. 1802 5

The overexpression of prosurvival members of the Bcl-2 family is commonly associated with the enhanced malignancy of hematological tumors. There has been great interest in a novel set of agents that are able to mimic the function of the BH3 domain by binding to the groove of Bcl-2-like proteins and initiating the cell death sequence. We sought to examine the efficacy of BH3 mimetics in a spontaneous mouse model of B-cell neoplasia. We evaluated the ability of the BH3 mimetics to preferentially target tumor cells while sparing normal cells. In addition, we examined the contributions of Bim and Puma to the sensitivity of tumor cells to the BH3 mimetics. We report here that two BH3 mimetics (HA-14-1 and BH3-I-2') were able to induce apoptosis of murine B-cell lymphoma cells in vitro and in vivo. Tumors that arose from transplantation of primary lymphoma cells regressed following 7 days of treatment with BH3-mimetic drugs. The long-term benefits of the transient treatment of tumor-bearing mice with the BH3 mimetics, however, could not be properly evaluated, due to the high levels of toxicity we observed in vivo with these drugs. Decreased expression of either Bim or Puma from B-cell tumor cells was able to protect these cells from the apoptosis induced by these BH3 mimetics, suggesting that they function through other means. We conclude that while the BH3-mimetic drugs are effective at inducing cell death of lymphoma cells in vitro and in vivo, their unclear molecular specificity and their ability to kill normal cells may limit their therapeutic uses in humans.
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PMID:Small-molecule inhibitors of Bcl-2 family proteins are able to induce tumor regression in a mouse model of pre-B-cell acute lymphocytic lymphoma. 1816 80

Overexpression of antiapoptotic members of the Bcl-2 family are observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying antiapoptotic function can potentially overcome this in-trinsic and acquired drug resistance. AT-101 is a BH3 mimetic known to be a potent inhibitor of antiapoptotic Bcl-2 family members including Bcl-2, Bcl-X(L), and Mcl-1. In vitro, AT-101 exhibits concentration- and time-dependent cytotoxicity against lymphoma and multiple myeloma cell lines, enhancing the activity of cytotoxic agents. The IC(50) for AT-101 is between 1 and 10 microM for a diverse panel of B-cell lymphomas. AT-101 was synergistic with carfilzomib (C), etoposide (E), doxorubicin (D), and 4-hydroxycyclophosphamide (4-HC) in mantle cell lymphoma (MCL) lines. In a transformed large B-cell lymphoma line (RL), AT-101 was synergistic when sequentially combined with 4-HC, but not when both drugs were added simultaneously. AT-101 also induced potent mitochondrial membrane depolarization (Delta Psi m) and apoptosis when combined with carfilzomib, but not with bortezomib in MCL. In severe combined immunodeficient (SCID) beige mouse models of drug-resistant B-cell lymphoma, 35 mg/kg per day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide (Cy) and rituximab (R) in a schedule-dependent manner enhanced the efficacy of the conventional therapy.
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PMID:Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma. 1850 36

Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery of ABT-737, a potent, small-molecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable, which would limit chronic single agent therapy and flexibility to dose in combination regimens. Here we report the biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (K(i)'s of <1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim), leading to the initiation of apoptosis within 2 hours posttreatment. In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in small-cell lung cancer and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility both as a single agent and in combination regimens.
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PMID:ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. 1845 Nov 70

Pro-survival proteins in the B-cell lymphoma-2 (Bcl-2) family have a defined specificity profile for their cell death-inducing BH3-only antagonists. Solution structures of myeloid cell leukaemia-1 (Mcl-1) in complex with the BH3 domains from Noxa and Puma, two proteins regulated by the tumour suppressor p53, show that they bind as amphipathic alpha-helices in the same hydrophobic groove of Mcl-1, using conserved residues for binding. Thermodynamic parameters for the interaction of Noxa, Puma and the related BH3 domains of Bmf, Bim, Bid and Bak with Mcl-1 were determined by calorimetry. These unstructured BH3 domains bind Mcl-1 with affinities that span 3 orders of magnitude, and binding is an enthalpically driven and entropy-enthalpy-compensated process. Alanine scanning analysis of Noxa demonstrated that only a subset of residues is required for interaction with Mcl-1, and these residues are localised to a short highly conserved sequence motif that defines the BH3 domain. Chemical shift mapping of Mcl-1:BH3 complexes showed that Mcl-1 engages all BH3 ligands in a similar way and that, in addition to changes in the immediate vicinity of the binding site, small molecule-wide structural adjustments accommodate ligand binding. Our studies show that unstructured peptides, such as the BH3 domains, behave like their structured counterparts and can bind tightly and selectively in an enthalpically driven process.
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PMID:Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1. 1858 38

Overexpression of antiapoptotic members of the Bcl-2 family is observed in approximately 80% of B-cell lymphomas, contributing to intrinsic and acquired drug resistance. Nullifying the antiapoptotic influence of these proteins can potentially overcome this resistance, and may complement conventional chemotherapy. ABT-737 is a BH3-only mimetic and potent inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-X(L), and Bcl-w. In vitro, ABT-737 exhibited concentration-dependent cytotoxicity against a broad panel of lymphoma cell lines including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). ABT-737 showed synergism when combined with the proteasome inhibitors bortezomib or carfilzomib in select lymphoma cell lines and induced potent mitochondrial membrane depolarization and apoptosis when combined with either. ABT-737 plus bortezomib also induced significant apoptosis in primary samples of MCL, DLBCL, and chronic lymphocytic leukemia (CLL) but no significant cytotoxic effect was observed in peripheral blood mononuclear cells from healthy donors. In severe combined immunodeficient beige mouse models of MCL, the addition of ABT-737 to bortezomib enhanced efficacy compared with either drug alone and with the control. Collectively, these data suggest that ABT-737 alone or in combination with a proteasome inhibitor represents a novel and potentially important platform for the treatment of B-cell malignancies.
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PMID:The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. 1859 85

In the present study, the toxicity of arsenic trioxide and lead acetate was assessed in adult hepatic stem cells induced in the 2-acetyl-aminofluorene/partial hepatectomy rat model. Isolated oval cells were incubated separately for 6 h with 40 muM each of arsenic trioxide and lead acetate. 3-(4,5-Dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay denoted significant time-dependent cell death in arsenic and lead treated oval cells. The degree of stress imposed by these metals was evidenced by induction of heat shock protein (HSP) 70 and HSP 90. Arsenic and lead were found to trigger apoptosis as revealed by DNA ladder formation, Western blots of apoptotic factors, and reverse transcriptase polymerase chain reaction analyses of bax and bcl-2. Results clearly indicate that both arsenic and lead induced apoptosis is caspase-mediated and accompanied by extracellular signal-regulated kinase (ERK) dephosphorylation. Full-length BH3-interacting-domain death agonist expression in presence of caspase 3 inhibitor unravels a direct involvement of caspase in As and Pb induced apoptosis. Expression patterns of apoptosis inducing factor, B cell lymphoma-2 (Bcl-2) antagonist of cell death, Bcl-2-associated X protein, and Bcl2 also signify mitochondrial regulation of apoptosis effected by lead and arsenic. It is concluded that stimulation of caspase cascade and simultaneous ERK dephosphorylation are the most significant operative pathways directly associated with apoptotic signals triggered by arsenic and lead in the oval cells.
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PMID:Arsenic trioxide and lead acetate induce apoptosis in adult rat hepatic stem cells. 1861 74


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