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)

PS-341, a potent and selective proteasome inhibitor, is the prototype for a new class of therapeutics that targets the ubiquitin-proteasome pathway. It is active as a single agent and potentiates chemotherapy and radiation in pre-clinical models. Early phase clinical studies have demonstrated tolerability and activity in multiple myeloma, lymphoma, prostate cancer and lung cancer. By its mechanism of inhibiting protein degradation, PS-341 targets a wide-range of pathways that are relevant to tumor progression and therapy resistance, and can directly modulate expression of cyclins, p27(Kip1), p53, NF-kappaB, Bcl-2 and Bax. PS-341 is currently in phase I/II clinical development in lung cancer. This paper will review the pre-clinical and clinical experience with PS-341 as it relates to lung cancer.
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PMID:Integration of the proteasome inhibitor PS-341 (Velcade) into the therapeutic approach to lung cancer. 1286 67

Novel agents that target the proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, have demonstrated remarkable therapeutic efficacy in multiple myeloma, a plasma cell malignancy. However, the mechanism by which these compounds act remains unknown. A signaling pathway called the unfolded protein response (UPR) allows cells to handle the proper folding of proteins. The transcription factor XBP-1, a regulator of the UPR, is also required for plasma cell differentiation, suggesting a link between the UPR and plasma cell differentiation. Here we show that proteasome inhibitors target XBP-1 and the UPR in myeloma cells. Proteasome inhibitors suppress the activity of the translumenal endoplasmic reticulum endoribonuclease/kinase, IRE1 alpha, to impair the generation of the active, spliced XBP-1 species and simultaneously stabilize the unspliced species that acts as a dominant negative. Myeloma cells rendered functionally deficient in XBP-1 undergo increased apoptosis in response to endoplasmic reticulum stress. Identification of compounds that target the activity of IRE1 alpha/XBP-1 may yield novel therapies for the treatment of multiple myeloma and other malignancies that rely on an intact UPR.
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PMID:Proteasome inhibitors disrupt the unfolded protein response in myeloma cells. 1290 39

Multiple myeloma is one of the 20 most frequent malignancies in Germany. Initial symptoms are usually non-specific. Assessment of bone marrow and laboratory data as well as imaging techniques are essential for diagnosis and prognostic evaluation. Data from molecular cytogenetics have led to a better understanding of the pathogenesis of multiple myeloma. Cytostatic therapy with alcylating agents and glucocorticoids prolongs the survival. High-dose therapy followed by transplantation of autologous hematopoietic stem cells improves prognosis for patients up to the age of 70. Currently, modifications of allogeneic hematopoietic stem cell transplantation, anti-angiogeneic and immunomodulatory drugs as well as proteasome inhibitors are evaluated in clinical trials. Supportive care has derived benefit from the introduction of new bisphosphonates.
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PMID:[Multiple myeloma. Diagnosis and therapy]. 1296 88

Genetic heterogeneity between individuals confounds the comparison of gene profiling of multiple myeloma (MM) cells versus normal plasma cells (PCs). To overcome this barrier, we compared the gene expression profile of CD138+ MM cells from a patient bone marrow (BM) sample with CD138+ PCs from a genetically identical twin BM sample using microarray profiling. Two hundred and ninety-six genes were up-regulated and 103 genes were down-regulated at least 2-fold in MM cells versus normal twin PCs. Highly expressed genes in MM cells included cell survival pathway genes such as mcl-1, dad-1, caspase 8, and FADD-like apoptosis regulator (FLIP); oncogenes/transcriptional factors such as Jun-D, Xbp-1, calmodulin, Calnexin, and FGFR-3; stress response and ubiquitin/proteasome pathway-related genes and various ribosomal genes reflecting increased metabolic and translational activity. Genes that were down-regulated in MM cells versus healthy twin PCs included RAD51, killer cell immunoglobulin-like receptor protein, and apoptotic protease activating factor. Microarray results were further confirmed by Western blot analyses, immunohistochemistry, fluorescent in situ hybridization (FISH), and functional assays of telomerase activity and bone marrow angiogenesis. This molecular profiling provides potential insights into mechanisms of malignant transformation in MM. For example, FGFR3, xbp-1, and both mcl-1 and dad-1 may mediate transformation, differentiation, and survival, respectively, and may have clinical implications. By identifying genes uniquely altered in MM cells compared with normal PCs in an identical genotypic background, the current study provides the framework to identify novel therapeutic targets.
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PMID:Identification of genes modulated in multiple myeloma using genetically identical twin samples. 1296 76

Multiple Myeloma is a hematologic malignancy characterized by the abnormal proliferation of plasma cells. Therapy for this disease has largely been palliative, and chances for long term survival after initiation of treatment have been quite limited. In the era of molecular therapies, a better understanding of the molecular biology resulting in the development of myeloma have shed light on a number of novel and potentially exciting therapeutic options for this disease which previously had limited options. This review will discuss some of the basic mechanisms of current therapy such as corticosteroids and alkylating agents, as well as developing such as the proteasome inhibitors, thalidomide and its analogs, arsenic trioxide, anti-sense technology, and others. The final section will assess the potential for new targeted approaches to treatment for mechanisms which have yet to be fully explored, and for agents which are in early phase I development
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PMID:Signal transduction and myeloma: new targets, new hope. 1450 98

Interactions between the small molecule Bcl-2 inhibitor HA14-1 and proteasome inhibitors, including bortezomib (Velcade; formerly known as PS-341) and MG-132, have been examined in human multiple myeloma cells. Sequential (but not simultaneous) exposure of MM.1S cells to bortezomib or MG-132 (10 h) followed by HA14-1 (8 h) resulted in a marked increase in mitochondrial injury (loss of DeltaPsim, cytochrome c, Smac/DIABLO, and apoptosis-inducing factor release), activation of procaspases-3, -8, and -9, and Bid, induction of apoptosis, and loss of clonogenicity. Similar interactions were observed in U266 and MM.1R dexamethasone-resistant myeloma cells. These events were associated with Bcl-2 cleavage, Bax, Bak, and Bad accumulation, mitochondrial translocation of Bax, abrogation of Mcl-1, Bcl-xL, and XIAP upregulation, and a marked induction of JNK and p53. Bortezomib/HA14-1 treatment triggered an increase in reactive oxygen species (ROS), which, along with apoptosis, was blocked by the free radical scavenger N-acetyl-L-cysteine (L-NAC). L-NAC also opposed bortezomib/HA14-1-mediated JNK activation, upregulation of p53 and Bax, and release of cytochrome c and Smac/DIABLO. Finally, bortezomib/HA14-1-mediated apoptosis was unaffected by exogenous IL-6. Together, these findings indicate that sequential exposure of myeloma cells to proteasome and small molecule Bcl-2 inhibitors such as HA14-1 may represent a novel therapeutic strategy in myeloma.
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PMID:The proteasome inhibitor bortezomib promotes mitochondrial injury and apoptosis induced by the small molecule Bcl-2 inhibitor HA14-1 in multiple myeloma cells. 1451 55

The proteasome plays a key role in regulating protein degradation in eukaryotic cells. A range of synthetic inhibitors of proteasome activity have been developed which have helped elucidate its role in the cell. These inhibitors have selectively induced apoptosis in malignant cells in vitro suggesting that the proteasome may be a novel therapeutic target. First generation proteasome inhibitors are currently showing promise in phase II/III clinical trials for patients with multiple myeloma.
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PMID:The proteasome: a novel therapeutic target in haematopoietic malignancy. 1453 Jan 69

Multiple myeloma, a B cell malignancy of the plasma cells, remains incurable. Advances in high-dose chemotherapy and stem cell transplantation have improved overall survival and event-free disease periods, but relapses are inevitable. New therapeutic agents have shown promising clinical use in patients with relapsed or refractory multiple myeloma. This article discusses the therapeutic applications of these novel agents with a focus on immunomodulatory drugs, proteasome inhibitors, and arsenic compounds.
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PMID:Understanding novel therapeutic agents for multiple myeloma. 1460 48

E3 ubiquitin ligases are a large family of proteins that can be classified into three major structurally distinct types: N-end rule E3s, E3s containing the HECT (Homology to E6AP C-Terminus) domain, and E3s with the RING (Really Interesting New Gene) finger, including its derivatives, the U- Box and the PHD (Plant Homeo-Domain). E3 ubiquitin ligases exist as single polypeptide or multimeric complexes. Together with ubiquitin activating enzyme E1 and ubiquitin conjugating enzyme E2, E3 ubiquitin ligases catalyze the ubiquitination of a variety of protein substrates for targeted degradation via the 26S proteasome. E3 ubiqutin ligases, therefore, play an essential role in regulation of many biological processes. Furthermore, E3s are enzymes that determine the specificity of protein substrates; they represent a class of "drugable" targets for pharmaceutical intervention. In this review, I will mainly focus on E3 ubiquitin ligases as potential cancer targets and discuss three of the most promising E3s, Mdm2/Hdm2, IAPs, and SCF, for their target rationales, target validation, and critical issues associated with them. These E3 ligases or their components are overexpressed in many human cancers and their inhibition leads to growth suppression or apoptosis. In addition, I will evaluate two current methodologies available for the high throughput screening for small molecular weight chemical inhibitors of the E3 ubiquitin ligases. Although targeting E3 ubiquitin ligases is still in its infancy, speedy approval of the general proteasome inhibitor, Velcade (bortezomib) by the FDA for the treatment of relapsed and refractory multiple myeloma suggests the promise of specific E3 inhibitors in anti-cancer therapy. Emerging technologies, such as siRNA, will provide a better validation of many E3s. It is anticipated that E3 ubiquitin ligases will represent an important new target platform for future mechanism-driven drug discovery.
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PMID:Targeting E3 ubiquitin ligases for cancer therapy. 1468 65

Targeting the ubiquitin-proteasome pathway has emerged as a promising approach for treating cancer. Bortezomib (VELCADE, formerly known as PS-341), a potent and reversible proteasome inhibitor, is being evaluated in clinical trials for treating multiple myeloma, and various other types of hematologic and solid tumors. Proteasome inhibitors are known to induce apoptosis in human cancer cells. Nevertheless, the mechanisms of apoptosis induced by proteasome inhibitors remain unclear. In this study, we investigated the role of p53 and its downstream targets in bortezomib-induced apoptosis in HCT116 human colon cancer cells. We demonstrated that bortezomib induced p53, and activated its downstream genes p21, PUMA and Bax in a p53-dependent fashion. However, apoptotic response to bortezomib was not affected by the deletion of p53. Surprisingly, we found that bortezomib-induced apoptosis was markedly enhanced in the p21-knockout cells, while significantly decreased in the BAX-knockout cells. Furthermore, in the cells deficient for both Bax and p21, apoptosis was restored to the level in the parental or the p53-deficient cells. The opposite effects of Bax and p21 were unrelated to the extent of proteasome inhibition, and were also observed in cells treated with different proteasome inhibitors. These results indicate that p53 downstream targets can collectively modulate apoptotic response to bortezomib and other proteasome inhibitors.
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PMID:Differential apoptotic response to the proteasome inhibitor Bortezomib [VELCADE, PS-341] in Bax-deficient and p21-deficient colon cancer cells. 1468 80


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