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

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.
 ...
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.
 ...
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.
 ...
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.
 ...
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.
 ...
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.
 ...
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

We show that multiple myeloma (MM), the second most commonly diagnosed hematologic malignancy, is responsive to hsp90 inhibitors in vitro and in a clinically relevant orthotopic in vivo model, even though this disease does not depend on HER2/neu, bcr/abl, androgen or estrogen receptors, or other hsp90 chaperoning clients which are hallmarks of tumor types traditionally viewed as attractive clinical settings for use of hsp90 inhibitors, such as the geldanamycin analog 17-AAG. This class of agents simultaneously suppresses in MM cells the expression and/or function of multiple levels of insulin-like growth factor receptor (IGF-1R) and interleukin-6 receptor (IL-6R) signaling (eg, IKK/NF-kappaB, PI-3K/Akt, and Raf/MAPK) and downstream effectors (eg, proteasome, telomerase, and HIF-1alpha activities). These pleiotropic proapoptotic effects allow hsp90 inhibitors to abrogate bone marrow stromal cell-derived protection on MM tumor cells, and sensitize them to other anticancer agents, including cytotoxic chemotherapy and the proteasome inhibitor bortezomib. These results indicate that hsp90 can be targeted therapeutically in neoplasias that may not express or depend on molecules previously considered to be the main hsp90 client proteins. This suggests a more general role for hsp90 in chaperoning tumor- or tissue-type-specific constellations of client proteins with critical involvement in proliferative and antiapoptotic cellular responses, and paves the way for more extensive future therapeutic applications of hsp90 inhibition in diverse neoplasias, including MM.
 ...
PMID:Antimyeloma activity of heat shock protein-90 inhibition. 1623 64

The ubiquitin-proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.
 ...
PMID:Proteasome inhibitors as therapeutics. 1625 Sep 7

More effective therapies are needed for non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Proteasome inhibitors are one class of molecularly targeted antineoplastic agents being investigated for these diseases. These agents block the activity of the 26S proteasome, which is responsible for the degradation of the vast majority of intracellular proteins and thus affect multiple signaling pathways within cells. Bortezomib is the first proteasome inhibitor to be evaluated in human studies and is approved for use in multiple myeloma. Bortezomib is now being investigated as a potential treatment for NSCLC and SCLC. Preclinical studies have shown that single-agent bortezomib causes growth inhibition and apoptosis in numerous NSCLC cell lines in vitro and has antitumor activity in vivo. Bortezomib affects the levels of several proteins known to be of significance in lung cancers. Studies of bortezomib in combination with other antitumor agents in vitro and in vivo demonstrate that these combination regimens can offer additive/synergistic effects compared with the single agents. Bortezomib has been investigated in combination with taxanes, gemcitabine, carboplatin, histone deactylase inhibitors, and other molecularly targeted agents in various NSCLC cell lines. The sequence of administration of the agents in preclinical combination regimens in vitro and in vivo has been shown to be of significance; further elucidation of the mechanism of efficacy of bortezomib in lung cancer is required. Numerous clinical studies have been carried out or are ongoing. Bortezomib has the potential to play a significant role in the future management of NSCLC and SCLC.
 ...
PMID:Preclinical data with bortezomib in lung cancer. 1625 Sep 27


<< Previous 1 2 3 4 5 6 7 8 9 10