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)

Bortezomib, one of the proteasome inhibitors, has been approved in the United States for multiple myeloma as a second-line chemotherapy. In Japan, bortezomib has been used for for phase I clinical trials for multiple myeloma. As the action mechanism, it has been proposed that bortezomib inhibits NF-kappaB via IkappaB alpha. It also demonstrated positive results for non-Hodgkin's lymphoma and non-small cell lung cancer, but not for colorectal cancer or chronic lymphocytic leukemia. The mechanism of drug resistance has been well analized. Bortezomib is very effective but still induces adverse effects including hypotension especially when there is an overdose. Medical oncologists or hematology/oncologists must exert due caution.
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PMID:[Proteasome inhibitors]. 1527 75

Primary effusion lymphomas (PELs) are a rare type of non-Hodgkin's lymphoma that are resistant to cytotoxic chemotherapy. PELs manifest constitutive activation of nuclear factor kappa B (NF-kappaB), and inhibition of NF-kappaB induces apoptosis of PELs and sensitizes to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced death. Bortezomib (PS-341), a peptidyl boronic acid inhibitor of the proteasome, is a potent agent against a wide range of hematologic malignancies and has been shown to inhibit NF-kappaB. Thus, we examined the cytotoxic effects of bortezomib alone and in combination with various drugs. Bortezomib potently inhibited NF-kappaB in PEL cells in a dose-dependent manner. In addition, bortezomib inhibited growth and induced apoptosis of PEL cell lines (IC(50) values of 3.4-5.0 nM). Results of drug interactions between bortezomib and chemotherapy (doxorubicin and Taxol) were schedule-dependent: synergistic interactions were generally observed when PEL cells were pretreated with bortezomib prior to chemotherapy, whereas additive or even antagonistic interactions occurred with chemotherapy pretreatment or simultaneous treatment with bortezomib and chemotherapy. Most schedules of bortezomib and dexamethasone were synergistic, although pretreatment with dexamethasone resulted in additive interactions. Effects of combinations of bortezomib and TRAIL were generally additive. Thus, bortezomib represents a promising potential therapy for the treatment of PEL.
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PMID:Antitumor effects of bortezomib (PS-341) on primary effusion lymphomas. 1534 45

The ubiquitin-proteasome pathway is responsible for degrading many critical regulatory proteins involved in immune and inflammatory responses, control of cell growth and apoptosis. Recently, proteasome inhibitors have emerged as promising new therapeutic agents in hematological malignancies. Here we show that Bortezomib (PS-341), a proteasome-inhibitor, inhibits cellular proliferation and induces apoptosis in cell lines derived from Primary Effusion Lymphoma (PEL), a subtype of non-Hodgkin's lymphoma associated with infection by human herpes virus 8 (HHV-8). Bortezomib demonstrated more cytotoxicity against PEL cells than against cell lines derived from multiple myeloma, a disease for which is in current clinical use. Apoptosis induced by Bortezomib was associated with inhibition of the classical and alternative NF-kappaB pathways, upregulation of p53, p21 and p27 and activation of caspase cascade. Finally, treatment of PEL cells with Bortezomib exerted a synergistic or additive cytotoxic effect in combination with chemotherapeutic drugs or TRAIL. Taken together, these findings suggest that Bortezomib represents a promising agent for the treatment of PEL.
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PMID:The proteasome inhibitor bortezomib (PS-341) inhibits growth and induces apoptosis in primary effusion lymphoma cells. 1590 93

Proteasome inhibition is a novel, targeted approach in cancer therapy. Both natural and synthetic proteasome inhibitors selectively penetrate cancer cells, disrupting the orderly destruction of key regulatory proteins involved in tumorigenesis and metastasis. Disrupting the orderly destruction of regulatory proteins causes an imbalance of these proteins within the cell, which interferes with the systematic activation of signaling pathways required to maintain tumor cell growth and survival; therefore, cellular replication is inhibited and apoptosis ensues. Bortezomib (PS-341, Velcade), the first proteasome inhibitor evaluated in human clinical trials, has been approved by the US Food and Drug Administration for use in patients with refractory or relapsed multiple myeloma. Preclinical study results show that bortezomib suppresses tumor cell growth, induces apoptosis, overcomes resistance to standard chemotherapy agents and radiation therapy, and inhibits angiogenesis. Phase I study results established the antitumor activity of bortezomib, administered alone or in combination with standard chemotherapy agents, in patients with advanced hematologic malignancies or solid tumors, usually without additive toxicities. The results of phase II studies further supported the antitumor activity of bortezomib in patients with refractory or relapsed multiple myeloma and non-Hodgkin's lymphoma; less impressive results were observed in patients with stage IV renal cell cancer. Studies evaluating bortezomib in earlier stages of multiple myeloma, including first-line therapy, are under way. Evidence suggests that certain prognostic factors, such as older age and bone marrow containing more than 50% plasma cells, may be useful in predicting response and survival time in multiple myeloma patients receiving bortezomib. Further studies of bortezomib are needed to establish its full spectrum of activity, the ideal regimens for various tumor types, and clinically useful prognostic indicators that predict successful outcomes.
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PMID:Discovery, Development, and clinical applications of bortezomib. 1568 97

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by [(3)H]thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G(0)-G(1) together with a marked up-regulation of p27(Kip1) by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21(Cip1) inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27(Kip1) was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor alpha cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.
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PMID:Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma. 1569 3

The most common indolent lymphoma, follicular lymphoma comprises 35% of adult non-Hodgkin's lymphoma (NHL) in the United States and 22% worldwide. Features associated with adverse outcome include age, male gender, disease stage, and performance status, with the International Prognostic Index being the most widely used risk classification system. Long-term disease-free survival is possible in select patient subgroups after treatment, but very late relapses suggest that quiescent lymphoma cells might be harbored for long periods of time. Radiation therapy is the mainstay of treatment for limited-stage follicular lymphoma, but there is some experience with chemotherapy and combined chemoradiation. When to initiate treatment in patients with advanced disease is controversial, but options include various combined chemotherapy regimens, monoclonal antibodies, radiolabeled antibodies, and bone marrow or stem cell transplantation. Future directions in the treatment of follicular lymphoma include vaccines, antisense therapy, and proteasome inhibitors.
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PMID:Follicular lymphoma: expanding therapeutic options. 1577 Aug 90

Mantle cell lymphoma (MCL) is a distinctive non-Hodgkin's lymphoma sub-type, characterized by over-expression of cyclin D1 as a consequence of chromosomal translocation t(11;14)(q13;q32). MCL remains an incurable disease, combining the unfavorable clinical features of aggressive and indolent lymphomas. The blastic variant of MCL, which is often associated with additional cytogenetic alterations, has an even worse prognosis and new treatment options are clearly needed. The 26S proteasome is a large multi-catalytic multi-protein complex, present in all eukaryotic cells. It is responsible for the degradation of a variety of short-lived proteins and exhibits a key position in cellular processes including apoptosis and cell cycle progression. Targeting the ubiquitin - proteasome pathway has only recently been identified as a promising new therapeutic option for cancer patients. Interestingly, an increased activity of the proteasome pathway has been described in MCL cells and the inhibition of the proteasome seems to be a promising therapeutic approach for this incurable disease.
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PMID:Targeting the proteasome in mantle cell lymphoma: a promising therapeutic approach. 1710 19

Recent advanced developments in our understanding of cancer cell biology have begun to generate a host of new targets that are proving to be valuable substrates for new drug development. One example includes our ever-increasing understanding of the complex biology surrounding the ubiquitin-proteasome pathway. For years there have been a variety of compounds used in the laboratory that have been shown to inhibit the proteasome, though many of these compounds have proven to be relative non-specific inhibitors of intracellular and proteasome proteases. The recent synthesis of 1 novel inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibition represents a new approach for the treatment of many forms of cancer, especially select hematologic malignancies. Bortezomib has been approved by the United States Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. In addition to myeloma, bortezomib has also shown promising activity in the treatment of select types of non-Hodgkin's lymphomas (NHLs). Several single-agent phase II clinical trials in patients with a host of different NHL histologies have demonstrated that bortezomib has reproducible activity in mantle-cell lymphoma (MCL) and follicular lymphoma (FL), with some suggestion of activity in marginal zone lymphoma. The promising activity in these smaller studies has led to a number of larger multicenter studies with bortezomib in combination with rituximab in MCL, FL, and marginal zone lymphoma. The collective early experience from these studies continues to support the activity of bortezomib in these histologies of NHL. Herein, some of the biologic rationale for using proteasome inhibitors in lymphoma as well as some of the clinical data from these promising studies are discussed.
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PMID:Marked clinical activity of the proteasome inhibitor bortezomib in patients with follicular and mantle-cell lymphoma. 1635 24

VELCADER (bortezomib, Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, NJ) is a first-in-class proteasome inhibitor developed specifically for use as an antineoplastic agent. Inhibition of the proteasome results in disruption of homeostatic mechanisms within the cell that can lead to cell death. Bortezomib's first indication, for the treatment of relapsed myeloma in patients who have received at least two prior treatments and progressed on their previous treatment, was based in part on the magnitude of activity demonstrated in phase II trials. Bortezomib is currently indicated for patients who have received at least one prior therapy in the United States and European Union, although patients in the European Union must have already undergone bone marrow transplantation or be unsuitable for the procedure. A phase III trial demonstrated the superiority of bortezomib over high-dose dexamethasone in response rate, time to progression, and survival in patients with myeloma who had relapsed after 1-3 prior therapies. Clinical development is ongoing to investigate its activity as monotherapy and in combination regimens for the treatment of non-Hodgkin's lymphoma, solid tumors, and earlier presentations of myeloma.
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PMID:Bortezomib: proteasome inhibition as an effective anticancer therapy. 1640 35

The ubiquitin-proteasome pathway is responsible for the vast majority of regulated eukaryotic intracellular proteolysis. Inhibition of the proteasome induces beneficial antitumour effects by blocking cell-cycle progression, inducing apoptosis and suppressing angiogenesis. Bortezomib is the first proteasome inhibitor to reach the clinical arena, where Phase I - III trials verified its activity against relapsed/refractory multiple myeloma. Testing is ongoing to determine bortezomib's role in front-line therapy of this plasma cell dyscrasia, as well as in non-Hodgkin's lymphoma, in which encouraging single-agent activity has been seen. Proteasome inhibition is also a rational strategy to overcome chemoresistance and induce chemosensitisation. Combinations of bortezomib and other agents have enhanced efficacy, and additional studies are probing the activity of several regimens in lymphoid and myeloid malignancies. The current state of knowledge about the activity of bortezomib, both alone and in combination with standard chemotherapeutics, as part of the emerging armamentarium against haematological malignancies is reviewed.
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PMID:Targeting the proteasome as a therapeutic strategy against haematological malignancies. 1643 92


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