Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Resveratrol (trans-3,4,5-trihydroxystilbene) has received attention for its potential chemopreventive and antitumor effects in experimental systems. Recent evidence suggests that paclitaxel, alone or in combination with other drugs, can be effectively used in the treatment of non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). This study investigated whether resveratrol can sensitize NHL and MM cell lines to paclitaxel-mediated apoptosis and to delineate the underlying molecular mechanism of sensitization. Both resveratrol and paclitaxel negatively modulated tumor cell growth by arresting the cells at the G(2)-M phase of the cell cycle. Low concentrations of resveratrol exerted a sensitizing effect on drug-refractory NHL and MM cells to apoptosis induced by paclitaxel. Resveratrol selectively down-regulated the expression of antiapoptotic proteins Bcl-x(L) and myeloid cell differentiation factor-1 (Mcl-1) and up-regulated the expression of proapoptotic proteins Bax and apoptosis protease activating factor-1 (Apaf-1). Paclitaxel down-regulated the expression of Bcl-x(L), Mcl-1, and cellular inhibitor of apoptosis protein-1 antiapoptotic proteins and up-regulated Bid and Apaf-1. Combination treatment resulted in apoptosis through the formation of tBid, mitochondrial membrane depolarization, cytosolic release of cytochrome c and Smac/DIABLO, activation of the caspase cascade, and cleavage of poly(adenosine diphosphate-ribose) polymerase. Combination of resveratrol with paclitaxel had minimal cytotoxicity against quiescent and mitogenically stimulated human peripheral blood mononuclear cells. Inhibition of Bcl-x(L) expression by resveratrol was critical for chemosensitization and its functional impairment mimics resveratrol-mediated sensitization to paclitaxel-induced apoptosis. Inhibition of Bcl-x(L) expression by resveratrol was due to the inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and diminished activator protein-1-dependent Bcl-x(L) expression. The findings by resveratrol were corroborated with inhibitors of the ERK1/2 pathway. This study demonstrates that in resistant NHL and MM cell lines resveratrol and paclitaxel selectively modify the expression of regulatory proteins in the apoptotic signaling pathway and the combination, via functional complementation, results in synergistic apoptotic activity.
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PMID:Resveratrol modifies the expression of apoptotic regulatory proteins and sensitizes non-Hodgkin's lymphoma and multiple myeloma cell lines to paclitaxel-induced apoptosis. 1474 77

Rituximab (Rituxan, IDEC-C2B8) has been shown to sensitize non-Hodgkin's lymphoma (NHL) cell lines to chemotherapeutic drug-induced apoptosis. Rituximab treatment of Bcl-2-deficient Ramos cells and Bcl-2-expressing Daudi cells selectively decreases Bcl-(xL) expression and sensitizes the cells to paclitaxel-induced apoptosis. This study delineates the signaling pathway involved in rituximab-mediated Bcl-(xL) down-regulation in Ramos and Daudi NHL B cells. We hypothesized that rituximab may interfere with the extracellular signal-regulated kinase (ERK) 1/2 pathway, leading to decreased Bcl-(xL) expression. Rituximab (20 microg/mL) inhibited the kinase activity of mitogen-activated protein kinase kinase (MEK) 1/2 and reduced the phosphorylation of the components of the ERK1/2 pathway (Raf-1, MEK1/2, and ERK1/2) and decreased activator protein-1 DNA binding activity and Bcl-(xL) gene expression. These events occurred with similar kinetics and were observed 3 to 6 hours after rituximab treatment. Rituximab-mediated effects were corroborated by using specific inhibitors of the ERK1/2 pathway, which also reduced Bcl-(xL) levels and sensitized the NHL B cells to paclitaxel-induced apoptosis. Previous findings implicated a negative regulatory role of the Raf-1 kinase inhibitor protein (RKIP) on the ERK1/2 pathway. Rituximab treatment of NHL B cells significantly up-regulated RKIP expression, thus interrupting the ERK1/2 signaling pathway through the physical association between Raf-1 and RKIP, which was concomitant with Bcl-(xL) down-regulation. These novel findings reveal a signaling pathway triggered by rituximab, whereby rituximab-mediated up-regulation of RKIP adversely regulates the activity of the ERK1/2 pathway, Bcl-(xL) expression, and subsequent chemosensitization of drug-refractory NHL B cells. The significance of these findings is discussed.
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PMID:Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin's lymphoma B cells by Rituximab. 1546 8

The clinical application of rituximab (chimeric mouse anti-human CD20 mAb, Rituxan, IDEC-C2B8), alone and/or combined with chemotherapy, has significantly ameliorated the treatment outcome of patients with relapsed and refractory low-grade or follicular non-Hodgkin's lymphoma (NHL). The exact in vivo mechanisms of action of rituximab are not fully understood, although antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis have been suggested. We have proposed that modifications of the cellular signaling pathways by rituximab may be crucial for its clinical response. The B-cell restricted cell surface phosphoprotein CD20 is involved in many cellular signaling events including proliferation, activation, differentiation, and apoptosis upon crosslinking. Monomeric rituximab chemosensitizes drug-resistant NHL cells via selective downregulation of antiapoptotic factors through the type II mitochondrial apoptotic pathway. Several signaling pathways are affected by rituximab which are implicated in the underlying molecular mechanisms of chemosensitization. ARL (acquired immunodeficiency syndrome (AIDS)-related lymphoma) and non-ARL cell lines have been examined as in vitro model systems. In ARL, rituximab diminishes the activity of the p38MAPK signaling pathway resulting in inhibition of the interleukin (IL)-10/IL-10R autocrine/paracrine cytokine autoregulatory loop leading to the inhibition of constitutive STAT-3 activity and subsequent downregulation of Bcl-2 expression leading to chemosensitization. Rituximab upregulates Raf-1 kinase inhibitor protein (RKIP) expression in non-ARL cells. Through physical association with Raf-1 and nuclear factor kappaB (NF-kappa B)-inducing kinase (NIK), RKIP negatively regulates two major survival pathways, namely, the extracellular signal-regulated kinase1/2 (ERK1/2) and the NF-kappa B pathways, respectively. Downmodulation of the ERK1/2 and NF-kappa B pathways inhibits the transcriptional activity of AP-1 and NF-kappa B transcription factors, respectively, both of which lead to the downregulation of Bcl-(xL) (Bcl-2 related gene (long alternatively spliced variant of Bcl-x gene)) transcription and expression and sensitization to drug-induced apoptosis. Bcl-(xL)-overexpressing cells corroborated the pivotal role of Bcl-(xL) in chemosensitization. The specificity of rituximab-mediated signaling and functional effects were corroborated by the use of specific pharmacological inhibitors. Many patients do not respond and/or relapse and the mechanisms of unresponsiveness are unknown. Rituximab-resistant B-NHL clones were generated to investigate the acquired resistance to rituximab-mediated signaling, and chemosensitization. Resistant clones display different phenotypic, genetic and functional properties compared to wild-type cells. This review summarizes the data highlighting a novel role of rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Studies presented herein also reveal several intracellular targets modified by rituximab, which can be exploited for therapeutic and prognostic purposes in the treatment of patients with rituximab- and drug-refractory NHL.
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PMID:Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention. 1578 36

Immunotherapy with rituximab (a chimeric anti-CD20 monoclonal antibody), alone or in combination with chemotherapy, has improved the treatment outcome of patients with non-Hodgkin's lymphoma (NHL), but the in vivo mechanisms by which rituximab exerts its effects have not been elucidated. The mechanisms underlying resistance are not known. In addition to the proposed actions mediated by rituximab (such as complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and apoptosis), rituximab may signal the tumor cells and inhibit constitutively activated survival signaling pathways (Raf-1-MEK1/2-ERK1/2, p38 MAPK, NF-kappaB, and Akt), resulting in inhibition of cell growth and of selectively anti-apoptotic gene products such as Bcl-2 and Bcl-(xL). The inhibition of these anti-apoptotic gene products by rituximab sensitizes drug-resistant tumor cells to apoptosis induced by a variety of cytotoxic chemotherapeutic drugs. Also, rituximab sensitizes NHL cells to apoptosis resulting from upregulation of death receptors, implicating a novel in vivo role of host involvement in rituximab-mediated effects. We have developed rituximab-resistant clones that do not respond to rituximab-mediated cell signaling. The clones exhibited hyperactivated cell survival pathways and overexpression of anti-apoptotic gene products and could not be chemosensitized by rituximab. Inhibitors of the survival signaling pathways reverse drug resistance in both wildtype cells and resistant clones. These findings identify several novel intracellular pathways modifyed by rituximab that sensitize NHL cells to both chemotherapy and immunotherapy, as well as several therapeutic targets whose modifications reverse resistance. These findings have clinical relevance for both prognosis and novel treatment strategies for patients with NHL.
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PMID:What signals are generated by anti-CD20 antibody therapy? 2042 15