Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with B non-Hodgkin's Lymphoma (NHL) initially respond to conventional chemotherapy. However, relapses and recurrences occur and the patients develop resistance to further treatment. Immunotherapeutic approaches have been considered in the treatment of such patients. Rituximab (chimeric anti-human CD20 monoclonal antibody) is the first anti-cancer monoclonal antibody approved by the FDA for the treatment of B-NHL. It has been used alone or in combination with chemotherapy, and the clinical response rates have been 50% and greater than 95%, respectively. The in vivo mechanism by which rituximab mediates its effects is not clear, though ADCC, CDC and apoptosis have been suggested and supported by several studies. However, many patients do not respond to rituximab or become refractory to rituximab treatment and the underlying mechanism of unresponsiveness is not known. This review describes various molecular signaling pathways modified by rituximab using in vitro B-NHL cell lines as model systems. The findings demonstrate that rituximab treatment modulates the p38 MAPK, the Raf-1/MEK/ERK1/2 and the NF-kappaB pathways. These modifications induced by rituximab were in large part responsible for the down-regulation of the anti-apoptotic gene products Bcl-2/Bcl-xL and chemosensitization of the drug-resistant B-NHL cell lines to various drug-induced apoptosis. Studies on the development of resistance to rituximab were investigated with rituximab-resistant B-NHL clones derived from rituximab-sensitive B-NHL cell lines. The molecular signaling pathways modified by rituximab revealed several novel intracellular targets whose modification could sensitize both rituximab-sensitive and rituximab-resistant B-NHL to drug-induced apoptosis. These in vitro findings provide new possibilities for improving the clinical effectiveness of rituximab as well as for circumventing its resistance.
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PMID:Rituximab-mediated chemosensitization of AIDS and non-AIDS non-Hodgkin's lymphoma. 1593 40

Preclinical studies have shown the potential antitumour efficacy of monoclonal antibodies (MAbs) directed to the epidermal growth factor receptor (EGFR). In this report, we investigated the cytotoxic effects of the MAb matuzumab (EMD 72000) towards A431 cells and compared it to cetuximab. While cetuximab induced cell cycle arrest and inhibited A431 cell proliferation, matuzumab did not. Both MAbs inhibited growth factor induced EGFR, HER2 and AKT phosphorylation; however, only cetuximab inhibited ERK 1/2 phosphorylation. Taken together, the data indicate that each antibody may elicit different responses on EGFR downstream signalling pathways with a distinct impact on A431 cell line survival. When combined, MAbs synergistically inhibited cell proliferation and induced EGFR down-regulation with a strong inhibition of ERK1/2 and AKT phosphorylation. In addition, both MAbs efficiently inhibited VEGF expression and induced ADCC, highlighting their therapeutic potential in vivo when used either as a single agent or in combination.
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PMID:Different antiproliferative effects of matuzumab and cetuximab in A431 cells are associated with persistent activity of the MAPK pathway. 1916 13

Treatment of patients with relapsed or refractory low grade follicular B-NHL lymphoma with rituximab (chimeric anti-CD20 mAb) has resulted in approximately 50% response rate. The mechanism underlying the failure of rituximab to affect the remaining 50% of the patients is not clear, though their tumors express CD20. The in vivo effector functions of rituximab include ADCC, CDC and seldom apoptosis. In addition, we have reported that rituximab signals the cells and inhibits several intracellular cell survival pathways that are responsible for the immuno and chemo-sensitizing effects of rituximab on resistant B-NHL cell lines. The objective of this study was to develop novel and fully humanized anti-CD20 monoclonal antibodies with enhanced effector functions and molecular signaling that may potentiate their therapeutic efficacy. Novel humanized anti-CD20 monoclonal antibodies were derived from a chimerized form of murine anti-CD20 1K11791, shown to exert a more potent ADCC, CDC and apoptotic activities compared to rituximab. A representative humanized monoclonal antibody, BM-ca was used to examine its biological effect and molecular signaling using Ramos B-NHL cell line as a model. The studies were also performed in parallel with rituximab treatment for comparison. Ramos cells were treated with various concentrations of BM-ca monoclonal antibody. Inhibition of cell proliferation was observed in a concentration-dependent manner, suggesting cell signal perturbations must have occurred. Compared to untreated cells, treatment with BM-ca inhibited both the constitutively activated NF-kappaB and p38 MAPK pathways, as assessed by inhibition of both phospho-p65 and phospho-IkappaBalpha and phospho-p38, respectively, but not the unphosphorylated forms. BM-ca significantly induced the expression of the metastasis suppressor and immune surveillance cancer gene product, Raf-1 kinase inhibitor protein (RKIP). These alterations resulted in inhibition of anti-apoptotic gene products and sensitized Ramos cells to apoptosis by CDDP. In comparison with rituximab, BM-ca showed qualitative and quantitative differences in the above analyses. These findings demonstrate that BM-ca triggers CD20 expressing B-NHL cells resulting in a significant alteration of several gene products that regulate cell growth and chemoresistance.
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PMID:Dysregulation of the cell survival/anti-apoptotic NF-kappaB pathway by the novel humanized BM-ca anti-CD20 mAb: implication in chemosensitization. 1988 51

IL-21 plays an important role in regulating immune response and controlling chronic viral infections. Recently, we reported its decreased serum concentrations and their immunological consequences in HIV-infected persons. In this study, we have investigated how exogenous IL-21 enhances NK cell responses in these persons. We show that the cytokine receptors are expressed equally on all NK cell subsets defined by expression of CD16 and CD56; the cytokine activates STAT-3, MAPK, and Akt to enhance NK cell functions; the STAT-3 activation plays a key role in constitutive and IL-21-mediated enhancement of NK cell functions; the cytokine increases expression of antiapoptotic proteins Bcl-2 and Bcl-X(L) and enhances viability of NK cells but has no effect on their proliferation; the cytokine enhances HIV-specific ADCC, secretory, and cytotoxic functions, as well as viability of NK cells from HIV-infected persons; it exerts its biological effects on NK cells with minimal stimulation of HIV-1 replication; and the cytokine-activated NK cells inhibit viral replication in cocultured, HIV-infected, autologous CD4(+) T cells in a perforin- and LFA-1-dependent manner. These data suggest that IL-21 may serve as a valuable therapeutic tool for enhancing NK cell responses and inhibiting viral replication in HIV-infected patients.
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PMID:IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication. 2010 65

The use of therapeutic monoclonal antibodies (mAbs) has revolutionized cancer treatment. The conjugation of mAbs to nanoparticles has been broadly exploited to improve the targeting efficiency of drug nanocarriers taking advantage of high binding efficacy and target selectivity of antibodies for specific cell receptors. However, the therapeutic implications of nanoconjugation have been poorly considered. In this study, half-chain fragments of the anti-EGFR mAb cetuximab were conjugated to colloidal nanoparticles originating stable nanoconjugates that were investigated as surrogates of therapeutic mAbs in triple negative breast cancer (TNBC). Three TNBC cell lines were selected according to EGFR expression, which regulates activation of MAPK/ERK and PI3K/Akt pathways, and to distinctive molecular profiling including KRAS, PTEN, and BRCA1 mutations normally associated with diverse sensitivity to treatment with cetuximab. The molecular mechanisms of action of nanoconjugated half-chain mAb, including cell targeting, interference with downstream signaling pathways, proliferation, cell cycle, and apoptosis, along with triggering of ADCC response, were investigated in detail in sensitive and resistant TNBC cells. We found that half-chain mAb nanoconjugation was able to enhance the therapeutic efficacy and improve the target selectivity against sensitive, but unexpectedly also resistant, TNBC cells. Viability assays and signaling transduction modulation suggested a role of BRCA1 mutation in TNBC resistance to cetuximab alone, whereas its effect could be circumvented using half-chain cetuximab nanoconjugates, suggesting that nanoconjugation not only improved the antibody activity but also exerted different mechanisms of action. Our results provide robust evidence of the potential of half-chain antibody nanoconjugates in the treatment of TNBC, which could offer a new paradigm for therapeutic antibody administration, potentially allowing improved curative efficiency and reduced minimal effective dosages in both sensitive and resistant tumors.
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PMID:Half-Chain Cetuximab Nanoconjugates Allow Multitarget Therapy of Triple Negative Breast Cancer. 3035 May 74