Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ubiquitin-proteasome pathway has a central role in selective degradation of intracellular proteins. Among the key proteins degraded by the system are those involved in the control of inflammation, cell cycle regulation and gene expression. With numerous important cellular pathways affected, derangements in the ubiquitin system were shown to result in a variety of human diseases including malignancies, neurodegenerative diseases and hereditary syndromes, and proteasome inhibition was implicated as a potential treatment for cancer and inflammatory conditions. Two proteasome inhibitors are currently under clinical evaluation for multiple myeloma and acute ischemic stroke. The ubiquitin system also has an important function in the immune and inflammatory response. It is involved in antigen processing and presentation to cytotoxic T cells, and the activation of nuclear factor-kappa B--the central transcription factor of the immune system. Since the proteasome is the central source of antigenic peptides that are presented to the immune system, some viruses, such as the Epstein-Barr virus, developed escape mechanisms that manipulate the ubiquitin-proteasome system in order to persist in the infected host. Understanding the mechanisms underlying the production of viral antigens by the ubiquitin-proteasome system may have therapeutic applications such as future development of vaccines.
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PMID:Immunologic aspects of protein degradation by the ubiquitin-proteasome system. 1527 34

Plasma cell disorders are not uncommonly reported in young patients with HIV infection. These disorders range from benign polyclonal hypergammaglobulinemia to indeterminate monoclonal gammopathy of unknown significance (MGUS) to malignant dyscrasias, including multiple myeloma and plasma cell leukemia. Hypergammaglobulinemia and oligoclonal banding had been the most frequently reported disorders in the pre-HAART era. In HIV-infected persons, the incidence of MGUS is reported to be around 2.5%, with an approximate 4.5-fold increased risk of multiple myeloma. Many of these HIV-infected patients had been treated with alkylator-based regimens, and these reports predate the current widespread use of thalidomide-dexamethasone combination treatment in multiple myeloma. Although the optimal therapy for an HIV-infected person might with plasma cell dyscrasia is yet to be defined, in the current era of HAART the otherwise healthy HIV-infected patient might be tested like an HIV-negative person. Consequently, treatment with immunomodulatory agents (eg, thalidomide) and proteasome inhibitors (eg, bortezomib) may also be worth considering. High-dose chemotherapy with an autologous peripheral blood stem cell transplant is increasingly being considered as consolidation therapy in the younger non-HIV-infected myeloma patient. In the next few years, it is anticipated that these approaches will be applied more frequently to HIV-infected persons with myeloma.
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PMID:Plasma cell disorders in HIV-infected patients: from benign gammopathy to multiple myeloma. 1528 66

Interferon-alpha (IFNalpha) is a recombinant protein widely used in the therapy of several neoplasms such as myeloma, renal cell carcinoma, epidermoid cervical and head and neck tumours and melanoma. IFNalpha, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of cancer cell growth and differentiation, affecting cellular communication and signal transduction pathways. However, the way by which tumour cell growth is directly suppressed by IFNalpha is not well known. Wide evidence exists on the possibility that cancer cells undergo apoptosis after the exposure to the cytokine. Here we will discuss data obtained by us and others on the post-translational regulation of the expression of proteins involved in the occurrence of apoptotic process such as tissue transglutaminase (tTG) or in the modulation of cell cycle such as the cyclin-dependent kinase inhibitor p27. This new way of regulation of p27 and tTG occurs through the modulation of their proteasome-dependent degradation induced by the cytokine. We will also review the involvement of protein synthesis machinery in the induction of cell growth inhibition by IFNalpha. In details, we will describe the effects of IFNalpha on the expression and activity of the protein kinase dependent from dsRNA (PKR) and on the eukaryotic initiation factor of protein synthesis 5A (eIF-5A) and their correlations with the regulation of cancer cell growth. These data strongly suggest that the antitumour activity of IFNalpha against human tumours could involve still unexplored mechanisms based on post-translational and translational control of the expression of proteins that regulate cell proliferation and apoptosis.
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PMID:Translational and post-translational modifications of proteins as a new mechanism of action of alpha-interferon: review article. 1529 Mar 47

Interferon-alpha (IFNalpha) is a recombinant protein widely used in the therapy of several neoplasms such as myeloma, renal cell carcinoma, epidermoid cervical and head and neck tumors, and melanoma. IFNalpha, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of cancer cell growth and differentiation, affecting cellular communication and signal transduction pathways. However, the way by which tumor cell growth is directly suppressed by IFNalpha is not well known. Wide evidence exists on the possibility that cancer cells undergo apoptosis after the exposure to the cytokine. Here we will review the consolidate signal transducer and activator of transcription (STAT)-dependent mechanism of action of IFNalpha. We will discuss data obtained by us and others on the triggering of the stress-dependent kinase pathway induced by IFNalpha and its correlations with the apoptotic process. The regulation of the expression of proteins involved in apoptosis occurrence will be also described. In this regard, IFNalpha is emerging as a post-translational controller of the intracellular levels of the apoptosis-related protein tissue transglutaminase (tTG). This new way of regulation of tTG occurs through the modulation of their proteasome-dependent degradation induced by the cytokine. Until today, inconsistent data have been obtained regarding the clinical effectiveness of IFNalpha in the therapy of solid tumors. In fact, the benefit of IFNalpha treatment is limited to some neoplasms while others are completely or partially resistant. The mechanisms of tumor resistance to IFNalpha have been studied in vitro. The alteration of JAK-STAT components of the IFNalpha-induced signaling, can be indeed a mechanism of resistance to IFN. However, we have recently described a reactive mechanism of protection of tumor cells from the apoptosis induced by IFNalpha dependent on the epidermal growth factor (EGF)-mediated Ras/extracellular signal regulated kinase (Erk) signaling. The involvement of the Ras-->Erk pathway in the protection of tumor cells from the apoptosis induced by IFNalpha is further demonstrated by both Ras inactivation by RASN17 transfection and mitogen extracellular signal regulated kinase 1 (Mek-1) inhibition by exposure to PD098059. These data strongly suggest that the specific disruption of the latter could be a useful approach to potentiate the antitumour activity of IFNalpha against human tumors based on the new mechanistic insights achieved in the last years.
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PMID:Alpha-interferon and its effects on signal transduction pathways. 1538 89

The highly conserved eukaryotic ubiquitin-proteasome system (UP-S) plays a pivotal role in protein homeostasis and is critical in regulating normal and cancer-related cellular processes. The hierarchical nature of the UP-S provides a rich source of molecular targets for specific intervention and has therefore arisen as a promising approach to innovative anticancer therapies. The first in class proteasome inhibitory agent Bortezomib (Velcade) has recently obtained regulatory approval for the treatment of multiple myeloma. Ubiquitin-mediated degradation is a complex process that is comprised of well defined steps involving ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s). Although a single E1 activates the ubiquitin conjugation machinery, a large number of E2 conjugating enzymes and E3 ligases are now known to exist. Proteins tagged with ubiquitin are subsequently recognised by the proteasome for digestion and fragmentation. The enzymatic nature, multitude of E3s and their specific substrate recognition predestines them as therapeutic targets. This article will review known inhibitors of the proteasome and their molecular mechanisms as well as ongoing developments and promising avenues for targeting substrate-specific E3 ligases that are likely to yield a new class of therapeutics that will serve and complement the armamentarium of anticancer drugs.
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PMID:The ubiquitin-mediated protein degradation pathway in cancer: therapeutic implications. 1545 46

This session addressed the use of proteasome inhibition therapy in multiple myeloma, specifically bortezomib. It also discussed various complications of multiple myeloma and cautions to be taken, specifically regarding osteolytic lesions and renal failure.
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PMID:Proteasome inhibition therapy: assessing the clinical implications in hematologic diseases. 1547 96

The neuron cytoplasmic protein gene product 9.5 (PGP9.5)/ubiquitin-C-terminal hydrolase 1 (UCHL-1) protein is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal of ubiquitin, and is involved in the processing of ubiquitin precursors and ubiquinated proteins. Although this molecule is known as a specific tissue marker for the neuroendocrine system, many reports have indicated that PGP9.5 is a marker for certain tumour types, such as cancer of the lung, colon, and pancreas. The expression of PGP9.5 in myeloma cells was examined. PGP9.5 seemed to be expressed specifically in myeloma cells as compared with other haematological malignant cells. In addition, in myeloma cells subjected to growth-factor starvation, the upregulation of PGP9.5 was observed in association with that of p27(Kip1), a cyclin-dependent-kinase inhibitor, although the upregulation caused by irradiation was milder. In contrast, the hypoxic culture of myeloma cells induced down-regulation of PGP9.5. These results suggested that PGP9.5 may be a good marker for myeloma among haematological malignancies. In addition, it may indicate certain cellular features of myeloma cells, such as sensitivity to proteasome inhibitors.
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PMID:Expression of protein gene product 9.5 (PGP9.5)/ubiquitin-C-terminal hydrolase 1 (UCHL-1) in human myeloma cells. 1549 Dec 88

The ubiquitin-proteasome pathway has a central role in selective degradation of intracellular proteins. Among the key proteins that are degraded by the system are those involved in the control of inflammation, cell cycle regulation, and gene expression. With so many important cellular pathways affected, derangements in the ubiquitin system have been shown to result in a variety of human diseases. Consequently, proteasome inhibition has a potential as a form of treatment for many human diseases such as cancer and inflammatory conditions. Two proteasome inhibitors, PS-341 and PS-519 are currently under clinical evaluation. PS-341 is currently being evaluated in phase III clinical trial for multiple myeloma, and PS-519 is now on a phase II trial for acute ischemic stroke. In addition, inhibition of the proteasome has been shown to be effective in several animal models for a variety of human diseases such as different malignancies, asthma, rheumatoid arthritis, and arterial restenosis. Future studies will be required to establish whether the promising animal studies could be successfully implicated in human disease states.
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PMID:[The ubiquitin system for intracellular protein degradation--involvement in human pathologies and therapeutic implications]. 1552 15

High-dose treatment (HDT) with autologous stem cell transplant(s) (ASCT) improved survival, when compared to standard treatment, in multiple myeloma patients. Although the superiority of HDT is clearly recognized by the medical community, what is less appreciated is the disproportionate benefit enjoyed (as a result of this approach) by various patient subgroups. As the clinical heterogeneity of myeloma can be currently traced to its underlying genetic features, prognostically different patient groups can be identified largely based on the presence of adverse cytogenetic abnormalities and high serum levels of lactate dehydrogenase at baseline (high-risk features). While HDT applied to high-risk patients leads to modest survival gains, the same treatment, as the backbone of a comprehensive approach, can be curative in a minority of low-risk patients. A third group of low-risk patients will enjoy rather prolonged (10-year) survival, interrupted, however, by responsive relapses. In a manner analogous to follicular lymphoma, this latter group may transform to a more aggressive disease, characterized by the new acquisition of adverse cytogenetic abnormalities. Improving the complete response rate in these patients, by integrating newer therapeutic agents, may increase their cure rate. Currently non-myeloablative, allogeneic transplants (and possibly proteasome inhibitors) are the most promising approaches for high-risk patients.
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PMID:Cure of myeloma: hype or reality? 1554 96

The proteasome plays a critical role in the degradation of proteins involved in the regulation of cell cycle, apoptosis, and angiogenesis. Bortezomib is the first in a new class of antineoplastic agents known as proteasome inhibitors to become available for clinical use. Bortezomib targets pathways relevant to tumor progression and therapy resistance and can directly modulate expression of cyclins, p27kip1, p53, nuclear factor-kB, Bcl-2, and Bax. In in vitro and in vivo, growth inhibition and apoptosis have been observed in tumor cells following exposure to bortezomib. Currently, bortezomib is approved for the treatment of patients with relapsed and/or refractory multiple myeloma who have received > or =2 therapies and progressed on their most recent therapy. Efforts are now being directed toward exploring the use of bortezomib in the treatment of advanced non-small-cell lung cancer (NSCLC). Clinical trials using bortezomib as monotherapy or in combinations, such as with taxanes, gemcitabine and platinums, and novel agents are under way, and preliminary results have demonstrated activity with bortezomib as a single agent and in combination with chemotherapy in advanced NSCLC. In addition, pharmacogenomics and biomarker analysis are being used in an attempt to identify tumor types likely to respond to treatment with bortezomib.
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PMID:Use of proteasome inhibition in the treatment of lung cancer. 1563 66


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