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)

Patients with metastatic melanoma or multiple myeloma have a dismal prognosis because these aggressive malignancies resist conventional treatment. A promising new oncologic approach uses molecularly targeted therapeutics that overcomes apoptotic resistance and, at the same time, achieves tumor selectivity. The unexpected selectivity of proteasome inhibition for inducing apoptosis in cancer cells, but not in normal cells, prompted us to define the mechanism of action for this class of drugs, including Food and Drug Administration-approved bortezomib. In this report, five melanoma cell lines and a myeloma cell line are treated with three different proteasome inhibitors (MG-132, lactacystin, and bortezomib), and the mechanism underlying the apoptotic pathway is defined. Following exposure to proteasome inhibitors, effective killing of human melanoma and myeloma cells, but not of normal proliferating melanocytes, was shown to involve p53-independent induction of the BH3-only protein NOXA. Induction of NOXA at the protein level was preceded by enhanced transcription of NOXA mRNA. Engagement of mitochondrial-based apoptotic pathway involved release of cytochrome c, second mitochondria-derived activator of caspases, and apoptosis-inducing factor, accompanied by a proteolytic cascade with processing of caspases 9, 3, and 8 and poly(ADP)-ribose polymerase. Blocking NOXA induction using an antisense (but not control) oligonucleotide reduced the apoptotic response by 30% to 50%, indicating a NOXA-dependent component in the overall killing of melanoma cells. These results provide a novel mechanism for overcoming the apoptotic resistance of tumor cells, and validate agents triggering NOXA induction as potential selective cancer therapeutics for life-threatening malignancies such as melanoma and multiple myeloma.
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PMID:Proteasome inhibitors trigger NOXA-mediated apoptosis in melanoma and myeloma cells. 1602 30

The proteasome is a ubiquitous enzyme complex that plays a critical role in the degradation of many proteins involved in cell cycle regulation, apoptosis and angiogenesis. Since these pathways are fundamental for cell survival and proliferation, particularly in cancer cells, the inhibition of proteasome is an attractive potential anticancer therapy. The present review will focus on the proteasome inhibitor bortezomib (Velcade, formerly PS-341; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA). Bortezomib is an extremely potent and selective proteasome inhibitor that shows strong activity in in vitro and in vivo laboratory studies against many solid and hematologic tumor types. Moreover, bortezomib, mainly by inhibition of the NF-kappaB pathway, has a chemosensitizing effect when administered together with other antitumoral drugs. Based on these results, bortezomib entered clinical phase I trials, alone or in combination with chemotherapy, that showed good tolerance at doses that achieved a desired degree of proteasome inhibition. Phase II studies showed high response rates in refractory multiple myeloma patients, which led to the accelerated approval of bortezomib by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for this indication. A phase III trial comparing bortezomib with dexamethasone in refractory/ relapsed multiple myeloma patients had to be halted due to a survival advantage in the bortezomib arm. Additional studies are focusing on the potential benefit of bortezomib in newly diagnosed multiple myeloma patients. In other solid and hematological malignancies, phase II studies with bortezomib alone or in combination with other agents are ongoing. Encouraging results, particularly in lung cancer and lymphoma, have been observed. The critical molecules or genes responsible for tumor sensitivity to bortezomib continue to be evaluated using novel technologies.
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PMID:Preclinical and clinical development of the proteasome inhibitor bortezomib in cancer treatment. 1608 28

Reccurent chromosomal translocation t(4;14) (p16.3;q32.3) occurs in patients with multiple myeloma (MM) and is associated with ectopic overexpression of fibroblast growth factor receptor 3 (FGFR3) that sometimes may contain the activation mutations such as K650E thanatophoric dysplasia type II (TDII). Although there have been significant advances in therapy for MM including the use of proteasome inhibitors, t(4;14) MM has a particularly poor prognosis and most patients still die from complications related to their disease or therapy. One potential therapeutic strategy is to inhibit FGFR3 in those myeloma patients that overexpress the receptor tyrosine kinase due to chromosomal translocation. Here we evaluated PKC412, a small molecule tyrosine kinase inhibitor, for treatment of FGFR3-induced hematopoietic malignancies. PKC412 inhibited kinase activation and proliferation of hematopoietic Ba/F3 cells transformed by FGFR3 TDII or a TEL-FGFR3 fusion. Similar results were obtained in PKC412 inhibition of several different t(4;14)-positive human MM cell lines. Furthermore, treatment with PKC412 resulted in a statistically significant prolongation of survival in murine bone marrow transplant models of FGFR3 TDII-induced pre-B cell lymphoma, or a peripheral T-cell lymphoma associated TEL-FGFR3 fusion-induced myeloproliferative disease. These data indicate that PKC412 may be a useful molecularly targeted therapy for MM associated with overexpression of FGFR3, and perhaps other diseases associated with dysregulation of FGFR3 or related mutants.
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PMID:FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. 1609 34

Proteasome inhibitors have emerged as a clinically important therapy for neoplastic disease, with velcade, an organoboron compound used extensively in multiple myeloma. Recently, (-)-epigallocatechin gallate has been found to be a potent inhibitor of the proteasomal chymotrypsin-like activity. Other compounds that inhibit angiogenesis and are active as chemopreventive agents, such as curcumin, also inhibit proteasome activity. We have screened natural product extracts using ras-transformed endothelial cells (SVR cells) as a bioassay, and found that extracts of mate tea (Ilex paraguayensis) inhibit the growth of these endothelial cells. The extract was fractionated and found to have novel cinnamate esters that inhibit proteasome activity. Based upon the structures of the compounds isolated from mate tea, we examined synthetic analogs of these compounds for proteasome activity. Cinnamic acid amides had no inhibitory activity against proteasomes, whereas cinnamate esters displayed the activity. Based upon these findings, preclinical and clinical trials of topical cinnamate esters as proteasome inhibitors are warranted for psoriasis and other inflammatory disorders.
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PMID:Naturally occurring proteasome inhibitors from mate tea (Ilex paraguayensis) serve as models for topical proteasome inhibitors. 1609 28

Multiple myeloma is an incurable malignancy diagnosed for approximately 15,000 individuals in the United States each year. The advances in high-dose chemotherapy and transplantation have improved the overall survival rates and allowed individuals to remain off therapy for longer periods, but relapses are inevitable. The novel proteasome inhibitor, bortezomib, is the first in its class to be approved for patients with relapsed multiple myeloma. This article discusses the proteasome pathway and its role in the regulation of cell growth and survival. During clinical trials, most side effects were manageable with appropriate interventions. The common toxicities are outlined in this article, along with symptom management guidelines for the infusion nurse. The role of the infusion-oncology nurse is vital to ensuring the safe and appropriate administration of bortezomib, and the nurse plays a key role in the ongoing care of these patients.
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PMID:Proteasome inhibition in cancer therapy. 1610 9

Multiple myeloma is a B-cell malignancy for which no curative therapies exist to date, despite enormous research efforts. The remarkable activity of the proteasome inhibitor bortezomib (PS-341, Velcade) observed in clinical trials of patients with relapsed refractory myeloma has led to investigations of the role of the ubiquitin-proteasome pathway in the pathogenesis of myeloma. Here we report a biochemical analysis of proteasome activity and composition in myeloma cells exposed to PS-341 in the presence or absence of cytokines present in the bone marrow milieu. We observed that the myeloma cell lines MM1.S, RPMI8226, and U266 contain active immunoproteasomes, the amount of which is enhanced by IFN-gamma and tumor necrosis factor-alpha. Using a radiolabeled active site-directed probe specific for proteasome catalytic subunits, we show that PS-341 targets the beta5 and beta1 subunits in a concentration-dependent manner. Furthermore, PS-341 also targeted the corresponding catalytic subunits of the immunoproteasome, beta5i and beta1i, respectively. These data suggest that PS-341 targets both normal and immunoproteasome species to a similar extent in myeloma cells.
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PMID:Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells. 1614 Sep 60

Recent advances in the treatment and management of haematological malignancies are due in large part to an improved understanding of the basic biology that drives tumour cell growth and survival. This improved understanding has led to the clinical study and approval of a number of different targeted agents across a number of different haematological tumours. This review of clinical data covers some of the exciting clinical advances that were reported at the recent American Society of Hematology meeting in San Diego, USA. This paper focuses on three important areas of biological research that has yielded clinical trials that have affected clinical outcomes. The areas covered include proteasome inhibition and myeloma, tyrosine kinase inhibitors that are directed at the BCR-ABL fusion protein and chronic myeloid leukaemia/acute lymphoblastic leukaemia, and FLT3 inhibitors and acute myeloid leukaemia acute lymphoblastic leukaemia therapy.
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PMID:Targeted therapy for haematological malignancies: clinical update from the American Society of Hematology, 2004. 1614

The proteasome is responsible for the degradation of intracellular proteins, including several involved in cell cycle control and the regulation of apoptosis. Preclinical studies have shown that the proteasome inhibitor bortezomib decreases proliferation, induces apoptosis, enhances the activity of chemotherapy and radiation, and reverses chemoresistance in a variety of hematologic and solid malignancy models in vitro and in vivo. Proteasome inhibition with bortezomib has specifically promoted apoptosis of tumor cells through the stabilization of p53, p21, p27, Bax, and IkappaBalpha, resulting in nuclear factor kappaB inhibition. Bortezomib was the first proteasome inhibitor to enter clinical trials. In two Phase II trials, SUMMIT and CREST, it was found that treatment with bortezomib, alone or in combination with dexamethasone, produced durable responses with meaningful survival benefits in patients with recurrent and/or refractory multiple myeloma. In the APEX Phase III trial, bortezomib produced significant survival benefits and improved response rates over high-dose dexamethasone at first recurrence and beyond in patients with multiple myeloma. Clinical trials evaluating the safety and activity of bortezomib alone or in combination regimens with dexamethasone, doxorubicin, melphalan, prednisone, and/or thalidomide in the treatment of patients with newly diagnosed multiple myeloma have shown encouraging results. Preliminary studies suggest that bortezomib may serve as induction therapy before stem cell transplantation. Proteasome inhibition with bortezomib also has shown activity with manageable toxicity in mantle cell and other lymphomas, leukemias, and solid malignancies, including nonsmall cell lung carcinoma. Further studies with bortezomib as monotherapy and in combination regimens in the treatment of solid and hematologic malignancies are warranted.
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PMID:Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies. 1617 3

Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin and CCI-779, have shown preclinical potential as therapy for multiple myeloma. By inhibiting expression of cell cycle proteins, these agents induce G1 arrest. However, by also inhibiting an mTOR-dependent serine phosphorylation of insulin receptor substrate-1 (IRS-1), they may enhance insulin-like growth factor-I (IGF-I) signaling and downstream phosphatidylinositol 3-kinase (PI3K)/AKT activation. This may be a particular problem in multiple myeloma where IGF-I-induced activation of AKT is an important antiapoptotic cascade. We, therefore, studied AKT activation in multiple myeloma cells treated with mTOR inhibitors. Rapamycin enhanced basal AKT activity, AKT phosphorylation, and PI3K activity in multiple myeloma cells and prolonged activation of AKT induced by exogenous IGF-I. CCI-779, used in a xenograft model, also resulted in multiple myeloma cell AKT activation in vivo. Blockade of IGF-I receptor function prevented rapamycin's activation of AKT. Furthermore, rapamycin prevented serine phosphorylation of IRS-1, enhanced IRS-1 association with IGF-I receptors, and prevented IRS-1 degradation. Although similarly blocking IRS-1 degradation, proteasome inhibitors did not activate AKT. Thus, mTOR inhibitors activate PI3-K/AKT in multiple myeloma cells; activation depends on basal IGF-R signaling; and enhanced IRS-1/IGF-I receptor interactions secondary to inhibited IRS-1 serine phosphorylation may play a role in activation of the cascade. In cotreatment experiments, rapamycin inhibited myeloma cell apoptosis induced by PS-341. These results provide a caveat for future use of mTOR inhibitors in myeloma patients if they are to be combined with apoptosis-inducing agents.
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PMID:Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. 1622 2

Consolidation with high-dose therapy followed by single or double autologous stem cell transplantation has improved response and survival of patients with multiple myeloma (MM), but the disease remains incurable. The emergence of novel agents offer potentially significant advances in the treatment of MM. Bortezomib, a selective inhibitor of the proteasome, has proven to be safe and effective in patients with relapsed and/or refractory MM as monotherapy in phase II/III clinical trials and has produced promising activity in combination regimens with cytotoxic agents. Bortezomib-based combination regimens have also exhibited clinical benefits with manageable toxicities and may ultimately lead to improvement in the duration of response and survival of patients in the first-line setting. High complete and near-complete response rates after 2-4 cycles of bortezomib-based induction therapy may improve outcome in autologous stem cell transplantation recipients. Bortezomib also appears to overcome the adverse prognostic impact of high b2-microglobulin levels and chromosome 13 deletion, as these patients at high risk have shown responses and improved survival with bortezomib therapy. Of interest, patients whose disease previously responded to bortezomib appear to retain sensitivity to the drug, and bortezomib is being explored in maintenance regimens. The use of bortezomib in MM therapy, including ongoing randomized phase III trials, is reviewed herein.
Clin Lymphoma Myeloma 2005 Sep
PMID:Emerging trends in the clinical use of bortezomib in multiple myeloma. 1623 45


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