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

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

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

PS-341 (bortezomib) represents a new class of therapeutics that targets the ubiquitin-proteasome pathway. It has broad-spectrum single-agent anticancer activity and can potentiate chemotherapy and radiation in preclinical models. Early phase clinical studies have shown tolerability and activity in multiple myeloma, lymphoma, prostate cancer, and lung cancers. By its mechanism of inhibiting protein degradation, PS-341 targets a wide range of pathways relevant to tumor progression and therapy resistance and can directly modulate expression of cyclins, p27(Kip1), p53, nuclear factor-kappaB, Bcl-2, and Bax. PS-341 is currently in phase I/II clinical development in both non-small cell lung cancer and small cell lung cancer. This article will review the preclinical and clinical experience with PS-341 as it relates to lung cancer.
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PMID:Proteasome inhibition with PS-341 (bortezomib) in lung cancer therapy. 1498 79

The multicatalytic proteinase complex, or proteasome, is responsible for the majority of regulated eukaryotic protein turnover through the ubiquitin-proteasome pathway. Bortezomib (Velcade, Millennium Pharmaceuticals, Inc.), the first drug specifically designed to target the proteasome, has recently entered the clinical arena. Previous preclinical studies showed that bortezomib had a unique cytotoxicity profile and that proteasome inhibition in vivo could be achieved safely with concomitant antitumor efficacy. In clinical studies, bortezomib has shown remarkable single-agent activity against relapsed and refractory multiple myeloma in both Phase I and II trials. Based on the latter, bortezomib has been approved by the US Food and Drug Administration for patients who have received two prior regimens and progressed on the second of these. Early results with bortezomib as a front-line therapy for multiple myeloma have shown a high response rate and further studies are ongoing. Preclinical studies support the possibility that modulation of proteasome function has great potential as a strategy for chemosensitization. Preliminary clinical trial results suggest that combinations using standard chemotherapeutics with bortezomib may have higher response rates in multiple myeloma than bortezomib as a single agent. Furthermore, these combinations may be able to recapture a response in patients whose disease was previously resistant to the standard agent, or bortezomib, or both. If borne out by additional studies, these results suggest that older treatment paradigms, in which drugs were used once but then discarded from the armamentarium upon disease progression, may need to be reassessed. Bortezomib may provide significant benefits to patients both alone and in combination with other agents and at several time points during the natural history of multiple myeloma.
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PMID:Bortezomib and its role in the management of patients with multiple myeloma. 1505 47

The ubiquitin-proteasome system plays a crucial role in eukaryotic cells in maintaining protein homeostasis. Through the disruption of a variety of pathways and cell cycle checkpoints, proteasome inhibition leads to apoptosis and in experimental models can overcome chemoresistance. Bortezomib is the first of its class of proteasome inhibitors tested in humans that showed promising activity in several tumor types, and especially in hematologic malignancies, in phase I studies. The remarkable results obtained in phase II studies in multiple myeloma (MM) led to its fast-track approval by the US Food and Drug Administration in May 2003 for relapsed MM. More recent observation also revealed promising activity in non-Hodgkin's lymphoma. This review will explore the rationale for the use of bortezomib in hematologic malignancies as well as provide an update on the results of ongoing studies and future directions for the use of this new agent in hematologic malignancies. The mechanism of action of bortezomib and its nonoverlapping toxicity profile make it a very appealing drug for combination with other chemotherapeutic or biologic agents. Bortezomib represents an excellent example of how progress in understanding the biology of cancer cells can impact clinical practice and lead toward a new era of rational therapeutics.
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PMID:Update on the proteasome inhibitor bortezomib in hematologic malignancies. 1507 15

The ubiquitin-proteasome pathway plays a central role in the targeted destruction of cellular proteins, including cell cycle regulatory proteins. Because these pathways are critical for the proliferation and survival of all cells, and in particular cancerous cells, proteasome inhibition is a potentially attractive anticancer therapy. Based on encouraging cytotoxic activity, bortezomib was the first proteasome inhibitor to be evaluated in clinical trials. Efficacy and safety results from a phase 2 clinical trial contributed to approval of bortezomib for use in patients with relapsed and refractory multiple myeloma who have received at least 2 prior therapies and have demonstrated disease progression on their last therapy.
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PMID:The development of proteasome inhibitors as anticancer drugs. 1514 49

Intracellular protein degradation is a tightly regulated process that in many cases is controlled by protein ubiquitylation. The ubiquitin pathway is a major route by which cells not only remove normal proteins at the appropriate time but also abnormally folded normal or mutant, cytoplasmic and membrane, proteins. This has led to a major impetus to identify constituents of the pathway. The key components that regulate substrate ubiquitylation are the ubiquitin-protein ligases. Ligases come in many forms, from single proteins to very large multiprotein complexes. Specificity of targeting can be modulated by the requirement for post-translational modifications such as phosphorylation, hydroxylation or oxidation of the substrate and, in some cases, the ligase itself. The requirement for substrate modification prior to ubiquitylation allows the same ligase to target different substrates within the same cell at different times. Abnormal intracellular protein processing is a common feature of many human diseases including neurodegenerative diseases and cancer. It may not represent the causative factor that initiates the disease process but may be a downstream regulator of the toxic effect. These abnormalities often arise from the loss of a key protein-protein interaction. As a consequence, mutated proteins can have very different half-lives from their normal counterparts. This can affect the levels of their activity and/or lead to the formation of protein aggregates (inclusion bodies/aggresomes). In this review, we aim to highlight examples of diseases where abnormal protein ubiquitylation is proposed to be a key regulator of the disease process. The recent success of the proteasome inhibitor Bortezomib (PS-341) for treatment of relapsed, refractory myeloma suggests that the modulation of individual ubiquitin-protein ligase activities with synthetic agents may represent a novel approach that has enormous potential for the treatment of a wide range of diseases.
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PMID:Ubiquitin-protein ligases--novel therapeutic targets? 1518 May 21

The elucidation of detailed new signaling pathways in normal cells and how their perturbation contributes to the development of the malignant phenotype has created innumerable venues for the development of novel drugs that can affect these targets in therapeutically meaningful ways. For example, our understanding of the complex biology underlying the ubiquitin-proteasome pathway in normal cells has recently led to the identification of specific agents capable of affecting this biology. Intuitively, one would not presume that inhibiting such a ubiquitous and essential biologic process, such as the ubiquitin-proteasome pathway, would lead to a new therapeutic strategy in cancer patients, although empirical evidence has suggested otherwise. The proteasome is a complex structure of many proteins, some of which are specific proteases, that play a critical role in regulating the balance of intracellular protein. Bortezomib, formerly known as PS-341, is a very potent and selective inhibitor of the chymotryptic-like enzymatic function residing in the 26S proteasome. Inhibition of this particular enzymatic activity has now been associated with an enormous panoply of different biologic effects, including everything from the regulation of nuclear factor-kappaB to the stabilization of cell-cycle regulatory proteins and the induction of apoptosis through the upregulation of specific proapoptotic proteins. Inhibiting this particular enzymatic function has now been associated with sometimes dramatic clinical effects in a variety of hematologic malignancies, including multiple myeloma and non-Hodgkin's lymphoma. This activity has led to the recent US Food and Drug Administration approval of bortezomib for the treatment of relapsed or refractory multiple myeloma. This activity has also spawned several clinical studies that have now clearly established activity in a host of different lymphoma subtypes, including the challenging mantle cell lymphomas. These data are simply the tip of the iceberg and will no doubt continue to provide fodder for many years of innovative scientific and clinical development. This development will likely lead to the eventual integration of this promising new class of molecules into the mainstream treatment of many hematologic malignancies, including myeloma and hopefully several different non-Hodgkin's lymphomas. Understanding how precisely to integrate these novel compounds will require us to learn more regarding the array of different biologic effects proteasome inhibitors have on the cell and how these effects can be further augmented with conventional chemotherapy drugs. The story is testament to the value of recognizing the importance of empiric observations in clinical and preclinical investigations.
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PMID:The emerging role of bortezomib in the treatment of indolent non-Hodgkin's and mantle cell lymphomas. 1523 4


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