Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular mechanisms responsible for lymphoma resistance to apoptosis often involve the bcl-2 pathway. In this study, we investigated the cell signaling pathways activated in bcl-2-overexpressing human mantle cell lymphoma cell lines (JVM-2 and Z-138) that have been treated with oblimersen, a molecular gene silencing strategy that effectively suppresses bcl-2 in vitro and in vivo. Z-138 cells expressed higher levels of bcl-2 and were more sensitive to the effects of bcl-2 silencing, mediated by oblimersen or bcl-2 small interfering RNA, in vitro. Tumors derived following injection of Z-138 cells were sensitive to oblimersen as judged by decreases in tumor growth rate and decreases in cell proliferation (as measured by Ki-67). Immunohistochemistry and Western blot analysis of oblimersen-treated Z-138 tumors revealed a dose-dependent decrease in bcl-2 levels and an associated increase in the proapoptotic proteins caspase-3 and caspase-9. Silencing bcl-2 in Z-138 xenografts revealed an associated dose-dependent suppression of bax, a decrease in nuclear factor-kappaB and phospho-nuclear factor-kappaB, and transient loss of p53 levels. Coimmunoprecipitation studies suggest that the latter observation is mediated by an association between bcl-2 and phospho-mdm2. Bcl-2 silencing also led to p27 down-regulation and coimmunoprecipitation studies point to a role for bcl-2 in regulation of p27 localization/degradation. Bcl-2 silencing was also correlated with loss of cyclin D1a protein levels but not cyclin D1b levels. Coimmunoprecipitation studies indicate that bcl-2 may mediate its effects on cyclin D1a via interaction with p38 mitogen-activated protein kinase as well as a previously unreported interaction between bcl-2 and cyclin D1a.
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PMID:Silencing Bcl-2 in models of mantle cell lymphoma is associated with decreases in cyclin D1, nuclear factor-kappaB, p53, bax, and p27 levels. 1837 22

Mantle cell lymphoma (MCL) represents 6% of non-Hodgkin lymphomas, but is one of the most active fields of clinical investigation. Unfortunately, there is still no standard or curative therapy in MCL. Front-line therapy appears to benefit from intensification either through high-dose therapy with stem cell transplant consolidation or dose-intense chemotherapy with hyperfractionated cyclophosphamide, vincristine, adriamycin/doxorubicin and dexamethasone/rituximab. Most patients still relapse and a multitude of novel agents are currently being tested in this setting, including proteasome inhibitors with bortezomib (the first of its class and the first US FDA-approved drug for MCL), mTOR inhibitors, Bcl-2 inhibitors, antiangiogenesis agents and histone deacetylase inhibitors among others. An obvious effort is needed to enroll patients on clinical trials, the design of which might benefit from pharmacogenomics and a better understanding of MCL biology and its diversity.
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PMID:Bortezomib in mantle cell lymphoma. 1840 30

The most common non-Hodgkin lymphomas in Uganda are neoplasms of B-cell derivation. The field of B-cell lymphoma immunophenotype has rapidly progressed because of the increasing availability of markers applicable to routine sections. Although the latter have allowed the identification of distinctive lymphoma entities in the developed countries, such approach has not yet been used in Uganda. One hundred twenty-nine formalin-fixed, paraffin-embedded tissue samples from the Department of Pathology of Makerere University were used for tissue micro-array (TMA) construction. Four-micrometer-thick sections were cut from TMAs and stained with hematoxylin and eosin and Giemsa. They were also used for immunohistochemistry and in situ hybridization. According to morphology and immunohistochemistry, lymphoid neoplasms were classified as Burkitt's lymphoma (BL) (95 cases), diffuse large B-cell lymphoma (19 cases), mantle cell lymphoma (4 cases), and B-cell lymphoblastic lymphoma (1 case). In BL, a homogeneous phenotype (CD10(+), Bcl-6(+), Bcl-2(-), MUM1/IRF4-, and Ki-67 approximately 100%) and a stable Epstein-Barr virus integration were found. A distinctive and unusual feature was the frequent plasma cellular differentiation, along with the positivity for CD30 and CD138 (recorded in 35 and 43 cases, respectively). According to our findings, most non-Hodgkin B-cell tumors in Uganda are endemic BLs followed by diffuse large B-cell lymphomas. The rest consist of rare but clinically important entities such as mantle cell lymphoma and B-cell lymphoblastic lymphoma. The availability of TMAs and immunohistochemistry has enabled us to precisely categorize tumors that have so far been diagnosed in Uganda as "high-grade/aggressive" lymphomas on the basis of cell morphology alone.
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PMID:B-cell non-Hodgkin lymphomas in Uganda: an immunohistochemical appraisal on tissue microarray. 1843 78

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

Arsenic trioxide (As(2)O(3)) has established clinical activity in acute promyelocytic leukaemia and has pre-clinical data suggesting activity in lymphoid malignancies. Cell death from As(2)O(3) may be the result of oxidative stress. Agents which deplete intracellular glutathione, such as ascorbic acid (AA), may potentiate arsenic-mediated apoptosis. This multi-institution phase II study investigated a novel dosing schedule of As(2)O(3) and AA in patients with relapsed or refractory lymphoid malignancies. Patients received As(2)O(3) 0.25 mg/kg iv and AA 1000 mg iv for five consecutive days during the first week of each cycle followed by twice weekly infusions during weeks 2-6. Cycles were repeated every 8 weeks. The primary end point was objective response. In a subset of patients, sequential levels of intracellular glutathione and measures of Bcl-2 and Bax gene expression were evaluated in peripheral blood mononuclear cells during treatment. Seventeen patients were enrolled between March 2002 and February 2004. The median age was 71, and the majority of enrolled patients had non-Hodgkin's lymphoma (12/17). Sixteen patients were evaluable, and one patient with mantle cell lymphoma achieved an unconfirmed complete response after five cycles of therapy for an overall response rate of 6%. The trial, which had been designed as a two-stage study, was closed after the first stage analysis due to lack of activity. Haematologic toxicities were the most commonly reported events in this heavily pre-treated population, and comprised the majority of grade 3 and 4 toxicities. Intracellular depletion of glutathione was not consistently observed during treatment. As(2)O(3) and AA in this novel dosing strategy was generally well tolerated but had limited activity in patients with relapsed and refractory lymphoid malignancies.
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PMID:Phase II study of arsenic trioxide and ascorbic acid for relapsed or refractory lymphoid malignancies: a Wisconsin Oncology Network study. 1866 98

We describe the association of 2 types of small B-cell lymphomas with different morphologic and immunophenotype patterns inside the same lymph node. Morphologically distinct zones were detected and studied with immunohistochemistry analyses. Most of the areas examined were characteristic of classic mantle cell lymphoma (CD20+, CD5+, cyclin D1+) with nodular and mantle zone areas. However, other areas had the morphologic and immunohistochemistry pattern of follicular lymphoma (CD20+, CD10+, Bcl2+). The diagnosis of both lymphomas was confirmed by polymerase chain reaction detection of both Bcl-1 MTC and Bcl-2 MBR rearrangements. DNA degradation in fixed tissue prevented a complete polymerase chain reaction analysis of immunoglobulin heavy chain rearrangements, but a single immunoglobulin H rearrangement was detected at the FR3 locus. These findings confirm the presence of a monoclonal cell population but do not demonstrate the same clonal origin for both lymphoma populations.
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PMID:Composite mantle cell and follicular lymphoma. A case report. 1875 98

ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-x(L), and Bcl-w, which is currently in phase I clinical trials. Previous work has shown that this compound has low nanomolar cell-killing activity in a variety of lymphoma and leukemia cell lines, many of which overexpress Bcl-2 through a variety of mechanisms. Rapamycin is a macrolide antibiotic that inhibits the mammalian target of rapamycin complex, leading to cell cycle arrest and inhibition of protein translation. Rapamycin (and its analogues) has shown activity in a variety of tumor cell lines primarily through induction of cell cycle arrest. Activity has also been shown clinically in mantle cell lymphoma and advanced renal cell carcinoma. Here, we show that treatment of the follicular lymphoma lines DoHH-2 and SuDHL-4 with 100 nmol/L rapamycin induces substantial G(0)-G(1) arrest. Addition of as little as 39 nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G(0) cells. Combination of these agents also led to a significant increase in Annexin V staining over ABT-263 alone. In xenograft models of these tumors, rapamycin induced a largely cytostatic response in the DoHH-2 and SuDHL-4 models. Coadministration with ABT-263 induced significant tumor regression, with DoHH-2 and SuDHL-4 tumors showing 100% overall response rates. Apoptosis in these tumors was significantly enhanced by combination therapy as measured by staining with an antibody specific for cleaved caspase-3. These data suggest that combination of ABT-263 and rapamycin or its analogues represents a promising therapeutic strategy for the treatment of lymphoma.
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PMID:ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. 1885 30

The ubiquitin-proteasome system has recently emerged as a major target for drug development in cancer therapy. The proteasome inhibitor bortezomib has clinical activity in multiple myeloma and mantle cell lymphoma. Here we report that Eeyarestatin I (EerI), a chemical inhibitor that blocks endoplasmic reticulum (ER)-associated protein degradation, has antitumor and biologic activities similar to bortezomib and can synergize with bortezomib. Like bortezomib, EerI-induced cytotoxicity requires the up-regulation of the Bcl-2 homology3 (BH3)-only pro-apoptotic protein NOXA. We further demonstrate that both EerI and bortezomib activate NOXA via an unanticipated mechanism that requires cooperation between two processes. First, these agents elicit an integrated stress response program at the ER to activate the CREB/ATF transcription factors ATF3 and ATF4. We show that ATF3 and ATF4 form a complex capable of binding to the NOXA promoter, which is required for NOXA activation. Second, EerI and bortezomib also block ubiquitination of histone H2A to relieve its inhibition on NOXA transcription. Our results identify a class of anticancer agents that integrate ER stress response with an epigenetic mechanism to induce cell death.
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PMID:ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells. 1916 57

Mantle cell lymphoma (MCL) is characterized by the uncontrolled overexpression of cyclin D1. Styryl sulfonyl compounds have shown potent antitumor activity against MCL by inducing cell-cycle arrest and apoptosis. However, the exact molecular mechanism by which these compounds function is yet to be elucidated. Here, we show that the prototypical styryl sulfonyl compound ON 01910.Na decreased cyclin D1 and c-Myc protein levels in MCL cells, whereas mRNA levels of cyclin D1 were minimally affected. Notably, ON 01910.Na suppressed eukaryotic translation initiation factor 4E (eIF4E)-mediated cyclin D1 mRNA translation, decreased levels of phosphorylated Akt, mammalian target of Rapamycin (mTOR) and eIF4E-binding protein (eIF4E-BP), lowered the cap site binding activity of eIF4E and directly inhibited activity of phosphatidylinositol-3 kinase (PI-3K). Analysis of apoptotic signaling pathways revealed that ON 01910.Na induced the release of cytochrome c from mitochondria, altered expression of Bcl-2 family of proteins and stimulated activation of caspases. Taken together, styryl sulfonyls can cause a rapid decrease of cyclin D1 by blocking cyclin D1 mRNA translation through inhibition of the PI-3K/Akt/mTOR/eIF4E-BP signaling pathway and triggering a cytochrome c-dependent apoptotic pathway in MCL cells.
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PMID:Styryl sulfonyl compounds inhibit translation of cyclin D1 in mantle cell lymphoma cells. 1919 27

Rituximab (RTX), a chimeric anti-CD20 antibody, is associated with direct induction of apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) with clinical efficacy in mantle cell lymphoma (MCL). Lenalidomide (LEN), a novel immunomodulatory agent, sensitizes tumor cells and enhances ADCC. Our study attempted to elucidate the mechanism of LEN-enhanced RTX-mediated cytotoxicity of MCL cells. We found that LEN and RTX induced growth inhibition of both cultured and fresh primary MCL cells. LEN enhanced RTX-induced apoptosis via upregulating phosphorylation of c-Jun N-terminal protein kinases (JNK), Bcl-2, Bad; increasing release of cytochrome-c; enhancing activation of caspase-3, -8, -9 and cleavage of PARP. Meanwhile, LEN activated NK cells and increased CD16 expression on CD56(low)CD16(+) NK cells. Whole PBMCs but not NK cell-depleted PBMCs treated with LEN augmented 30% of RTX-dependent cytotoxicity. Daily treatment with LEN increased NK cells by 10-folds in SCID mice, and combination of LEN and RTX decreased tumor burden and prolonged survival of MCL-bearing SCID mice. Taken together, our study demonstrates that LEN plus RTX provides a synergistically therapeutic effect on MCL cells by enhancing apoptosis and RTX-dependent NK cell-mediated cytotoxicity and may be an optimal combination in the clinical trial of relapsed or refractory MCL.
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PMID:Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo. 1956 49


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