Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphomas characterized by the chromosomal translocation t(11;14)(q13;q32) and nuclear cyclin D1 overexpression in the vast majority of cases. Most patients present with advanced stage disease, often with extranodal dissemination, and pursue an aggressive clinical course in the majority of cases. Recent improvement has been achieved by the successful introduction of monoclonal antibodies and dose-intensified approaches including autologous stem cell transplantation (ASCT) strategies. With the exception of allogeneic hematopoietic stem cell transplantation, current treatment approaches are non-curative and the corresponding survival curves are characterized by a delayed, but continuous decline and a median survival of 4 to 6 years. However, recently a subset (15%) of long-term survivors have been identified with a rather indolent clinical course even after conventional treatment strategies only. Emerging strategies such as proteasome inhibitors, IMIDs, mTOR inhibitors and others are based on the dysregulated control of cell cycle machinery and impaired apoptotic pathways. Monotherapy of these compounds achieves efficacy comparable to conventional chemotherapy in relapsed MCL, and combination strategies are currently being investigated in numerous trials; however, their introduction into clinical practice and current treatment algorithms remains a challenge.
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PMID:Current treatment standards and emerging strategies in mantle cell lymphoma. 2000 39

Mantle cell lymphoma (MCL) is a distinct histologic subtype of B cell non-Hodgkins lymphoma (NHL) associated with an aggressive clinical course. Inhibition of the ubiquitin-proteasome pathway modulates survival and proliferation signals in MCL and has shown clinical benefit in this disease. This has provided rationale for exploring combination regimens with B-cell selective immunotherapies such as rituximab. In this study, we examined the effects of combined treatment with bortezomib and rituximab on patient-derived MCL cell lines (Jeko, Mino, SP53) and tumor samples from patients with MCL where we validate reversible proteasome inhibition concurrent with cell cycle arrest and additive induction of apoptosis. When MCL cells were exposed to single agent bortezomib or combination bortezomib/rituximab, caspase dependent and independent apoptosis was observed. Single agent bortezomib or rituximab treatment of Mino and Jeko cell lines and patient samples resulted in decreased levels of nuclear NFkappaB complex(es) capable of binding p65 consensus oligonucleotides, and this decrease was enhanced by the combination. Constitutive activation of the Akt pathway was also diminished with bortezomib alone or in combination with rituximab. On the basis of in vitro data demonstrating additive apoptosis and enhanced NFkappaB and phosphorylated Akt depletion in MCL with combination bortezomib plus rituximab, a phase II trial of bortezomib-rituximab in patients with relapsed/refractory MCL is underway.
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PMID:Combination bortezomib and rituximab treatment affects multiple survival and death pathways to promote apoptosis in mantle cell lymphoma. 2004 72

In mouse models and cell lines, murine double minute 2 (MDM2) and MDM4 have been shown to synergistically promote proteasome-mediated degradation of p21 and p53. MDM4 also inhibits p53-mediated transcriptional activation of p21. p53 expression results in increased p21 expression, a negative cell-cycle regulatory protein and an inhibitor of cyclin D1. As mantle cell lymphoma is characterized by cyclin D1 overexpression, we assessed for human homolog of MDM4 (HDM4) expression and its effect on p21 in mantle cell lymphoma. Using immunohistochemical methods, in reactive lymph nodes (n=19) germinal center cells strongly expressed HDM4 in the nucleus and the cytoplasm, but mantle zone B-cells were only dimly positive. In mantle cell lymphoma tumors, aberrant HDM4 nuclear expression was observed in 18 of 19 (95%) cases. In contrast, HDM4 in other B-cell non-Hodgkin lymphoma types retained its normal pattern of expression. To further characterize the differential upregulation of HDM4 in mantle cell lymphoma, HDM4 was assessed by quantitative real-time polymerase chain reaction in four mantle cell lymphoma cell lines (Granta 519, Z-138, SP-53, and Mino) and six mantle cell lymphoma tumors. Both the splicing variant HDM4-S, containing only the p53-binding domain, and full length HDM4 were increased compared with normal CD19+ B-cells (P<0.05). Using small interfering RNA to inhibit HDM4 in the SP53 and Mino cell lines showed increased p21 and active caspase-3, the latter indicating increased apoptosis. Our results show that HDM4 is overexpressed in mantle cell lymphoma and, at least in part, exerts its effect by suppressing p21 expression, thereby enhancing cell-cycle progression. Inhibition of HDM4 may serve as a potential approach in the design of therapy for patients with mantle cell lymphoma.
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PMID:HDM4 is overexpressed in mantle cell lymphoma and its inhibition induces p21 expression and apoptosis. 2006 13

Proteases play a key role in various pathological processes and several protease inhibitors are already available for treatment. DUBs (deubiquitinating enzymes) constitute one of the largest classes of human proteases and are key effectors of the ubiquitin-proteasome system. This pathway regulating cellular protein turnover has been implicated in the pathogenesis of many human diseases, including neurodegenerative disorders, viral diseases and cancer. The therapeutic efficacy of the proteasome inhibitor Velcade (bortezomib) for treating multiple myeloma and mantle cell lymphoma establishes this system as a valid target for cancer treatment. A promising alternative to targeting the proteasome itself would be to target the upstream, ubiquitin conjugation/deconjugation system, to generate more specific, less toxic anticancer agents. Advances in small molecule-based inhibitors specifically targeting DUBs are presented in this review.
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PMID:The therapeutic potential of deubiquitinating enzyme inhibitors. 2007 48

The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection for the treatment of multiple myeloma and recurring mantle cell lymphoma. Consequently, several groups are pursuing the development of additional small-molecule proteasome inhibitors for both hematologic and solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation proteasome inhibitor that is in phase I clinical development. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib. MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications.
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PMID:Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. 2016 34

Proteasome inhibitors are emerging as a new class of cancer therapeutics, and bortezomib has shown promise in the treatment of multiple myeloma and mantle cell lymphoma. However, bortezomib has failed to have an effect in preclinical models of glioma. NPI-0052 is a new generation of proteasome inhibitors with increased potency and strong inhibition of all three catalytic activities of the 26S proteasome. In this article, we test the antitumor efficacy of NPI-0052 against glioma, as a single agent and in combination with temozolomide and radiation using five different glioma lines. The intrinsic radiation sensitivities differed for all the lines and correlated with their PTEN expression status. In vitro, NPI-0052 showed a dose-dependent toxicity, and its combination with temozolomide resulted in radiosensitization of only the cell lines with a mutated p53. The effect of NPI-0052 as a single agent on glioma xenografts in vivo was only modest in controlling tumor growth, and it failed to radiosensitize the glioma xenografts to fractionated radiation. We conclude that NPI-0052 is not a suitable drug for the treatment of malignant gliomas despite its efficacy in other cancer types.
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PMID:Differential Effects of the Proteasome Inhibitor NPI-0052 against Glioma Cells. 2016 95

The search for proteasome inhibitors began fifteen years ago. These inhibitors proved to be powerful tools for investigating many important cellular processes regulated by the ubiquitin-proteasome pathway. Targeting the proteasome pathway can also lead to new treatments for disorders like cancer, muscular dystrophies, inflammation and immune diseases. This is already true for cancer; the FDA approved bortezomib, a potent proteasome inhibitor, for treating multiple myeloma in 2003, and mantle cell lymphoma in 2006. The chemical structures identified in some of the early proteasome inhibitors have led to the development of new anti-cancer drugs (CEP-18770, Carfilzomib, NPI-0052). All these molecules are covalent bonding inhibitors that react with the catalytic Thr1-O(gamma) of the three types of active site. This review covers recent developments in medicinal chemistry of natural and synthetic proteasome inhibitors. Advances in non-covalent inhibitors that have no reactive group will be highlighted as they should minimize side-effects. New structures and new modes of action have been recently identified that open the door to new drug candidates for treating a range of diseases.
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PMID:Proteasome inhibitors: recent advances and new perspectives in medicinal chemistry. 2016 55

The ubiquitin-proteasome complex is an important molecular target for the design of novel chemotherapeutics. This complex plays a critical role in signal transduction pathways important for tumor cell growth and survival, cell-cycle control, transcriptional regulation, and the modulation of cellular stress responses to endogenous and exogenous stimuli. The sensitivity of transformed cells to proteasome inhibitors and the successful design of treatment protocols with tolerable, albeit narrow, therapeutic indices have made proteasome inhibition a viable strategy for cancer treatment. Clinical validation of the proteasome as a molecular target was achieved with the approval of bortezomib, a boronic acid proteasome inhibitor, for the treatment of multiple myeloma and mantle cell lymphoma. Several "next-generation" proteasome inhibitors (carfilzomib and PR-047, NPI-0052, and CEP-18770) representing distinct structural classes (peptidyl epoxyketones, beta-lactones, and peptidyl boronic acids, respectively), mechanisms of action, pharmacological and pharmacodynamic activity profiles, and therapeutic indices have now entered clinical development. These agents may expand the clinical utility of proteasome inhibitors for the treatment of solid tumors and for specific non-oncological, i.e., inflammatory disease, indications as well. This chapter addresses the biology of the proteasome, the medicinal chemistry and mechanisms of action of proteasome inhibitors currently in clinical development, the preclinical and clinical pharmacological and safety profiles of bortezomib and the newer compounds against hematological and solid tumors. Future directions for research and other applications for this novel class of therapeutics agents are considered in this chapter.
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PMID:The development and pharmacology of proteasome inhibitors for the management and treatment of cancer. 2023 Jul 60

Combination chemotherapy forms the backbone of cancer treatment. There is a need for new drug combinations for the treatment of mantle cell lymphoma (MCL). Herein, we show that gallium maltolate, a novel gallium compound, synergizes with bortezomib, a proteasome inhibitor, to induce cell death in MCL Granta cells. Cells exposed to either agent displayed caspase-3 activation, a loss of mitochondrial membrane potential, and a decrease in chymotrypsin-like activity. These effects were increased with both agents in combination. Our results show for the first time that the proteasome may be a target for gallium maltolate and suggest that the therapeutic potential of combination bortezomib and gallium maltolate warrants further investigation.
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PMID:A novel gallium compound synergistically enhances bortezomib-induced apoptosis in mantle cell lymphoma cells. 2033 13

Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma (NHL) entity. The translocation between chromosomes 11 and 14 is the cytogenetics hallmark of MCL. This translocation leads to the dysregulation of the CCDN1 gene, and overexpression of cyclin D1 which promotes cell cycling. Despite a classical phenotype (CD19+, CD20+, CD5+, CCND1+, CD10-, CD23-, Bcl-2+, Ig at the membrane, mainly IgM), MCL is not a homogeneous disease and several cytological, phenotypic, cytogenetic and clinical variants have been described. MCL represents 5 % of NHLs with its incidence constantly increasing over the last years. Median age at diagnosis is 68 years. Stage III-IV disease is observed in more than 80 % of patients at presentation, with intestinal and bone marrow being the most frequently involved organs, while the spleen is enlarged in half of cases. Intensive strategies including high-dose chemotherapy, followed by autologous stem cell transplantation have significantly improved the outcome of MCL patients. Median overall survival rate increased from 3 to 5 years during the last decade. At present, induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard regimen in younger patients. However, most of MCL patients will experience relapse. Thus, close monitoring of minimal residual disease (currently under evaluation) may represent a valuable tool for assessment of disease response during follow-up. Future innovative therapies that are being presently investigated in prospective trials include transduction pathways inhibitors, proteasome inhibitors, pro-apoptotic molecules, immunotherapy and/or radiolabeled immunotherapy, and will likely open a new era for targeted therapies in MCL.
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PMID:[Mantle cell lymphoma: an overview from diagnosis to future therapies]. 2048 92


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