Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The ubiquitin-proteasome pathway is a principal intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies since several cell cycle regulators and modulators of apoptosis are degraded through this pathway. The current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the US Food and Drug Administration for the treatment of advanced multiple myeloma, is reviewed. Particular emphasis is placed on the preclinical 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 an appraisal of possible uses in other hematologic malignancies, such as non-Hodgkin's lymphomas.
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PMID:Proteasome inhibition as a therapeutic strategy for hematologic malignancies. 1600 54

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.
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PMID:Proteasome inhibitors as therapeutics. 1625 Sep 7

The validation of the ubiquitin-proteasome pathway as a target for therapy of hematological malignancies stands out as one salient example of the ability to translate laboratory-based findings from the bench to the bedside. Preclinical studies showed that proteasome inhibitors had significant activity against models of non-Hodgkin lymphoma and multiple myeloma, and identified some of the relevant mechanisms of action. These led to phase I through III trials of the first clinically available proteasome inhibitor, bortezomib, which confirmed its activity as a single agent in these diseases. Modulation of proteasome function was then found to be a rational approach to achieve both chemosensitization in vitro and in vivo, as well as to overcome chemotherapy resistance. Based on these findings, first-generation bortezomib-based regimens incorporating traditional chemotherapeutics such as alkylating agents, anthracyclines, immunomodulatory agents, or steroids have been evaluated, and many show promise of enhanced clinical anti-tumor efficacy. Further studies of the pro-and anti-apoptotic actions of proteasome inhibitors, and of their effects on gene and protein expression profiles, suggest that novel agents, such as those targeting the heat shock protein pathways, are exciting candidates for incorporation into these combinations. Phase I trials to test these concepts are just beginning, but have already shown some encouraging results. Finally, novel proteasome inhibitors are being developed with unique properties that may also have therapeutic applications. Taken together, these studies demonstrate the power of rational drug design and development to provide novel, effective therapies for patients with hematological malignancies.
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PMID:The ubiquitin proteasome pathway from bench to bedside. 1630 84

Recent advanced developments in our understanding of cancer cell biology have begun to generate a host of new targets that are proving to be valuable substrates for new drug development. One example includes our ever-increasing understanding of the complex biology surrounding the ubiquitin-proteasome pathway. For years there have been a variety of compounds used in the laboratory that have been shown to inhibit the proteasome, though many of these compounds have proven to be relative non-specific inhibitors of intracellular and proteasome proteases. The recent synthesis of 1 novel inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibition represents a new approach for the treatment of many forms of cancer, especially select hematologic malignancies. Bortezomib has been approved by the United States Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. In addition to myeloma, bortezomib has also shown promising activity in the treatment of select types of non-Hodgkin's lymphomas (NHLs). Several single-agent phase II clinical trials in patients with a host of different NHL histologies have demonstrated that bortezomib has reproducible activity in mantle-cell lymphoma (MCL) and follicular lymphoma (FL), with some suggestion of activity in marginal zone lymphoma. The promising activity in these smaller studies has led to a number of larger multicenter studies with bortezomib in combination with rituximab in MCL, FL, and marginal zone lymphoma. The collective early experience from these studies continues to support the activity of bortezomib in these histologies of NHL. Herein, some of the biologic rationale for using proteasome inhibitors in lymphoma as well as some of the clinical data from these promising studies are discussed.
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PMID:Marked clinical activity of the proteasome inhibitor bortezomib in patients with follicular and mantle-cell lymphoma. 1635 24

The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by downregulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer.
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PMID:The proteasome and proteasome inhibitors in cancer therapy. 1640 3

Recent advances in understanding the complex biology of the ubiquitin-proteasome pathway have led to the identification of many potentially 'drugable' targets within this pathway. One such inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibitors represent a new approach for the treatment of many forms of cancer, especially select hematological malignancies. The proteasome plays an important role in regulating the availability of different intracellular proteins. While only some of the consequences of inhibiting this activity are understood, a growing amount of data suggests that inhibition of the proteasome is associated with a remarkable panoply of different biological effects that include cell cycle arrest, apoptosis, changes in cell surface adhesion markers, and an increased sensitivity to standard chemotherapy and radiation therapy. Bortezomib was recently approved by the US FDA for the treatment of relapsed or refractory multiple myeloma. In addition, bortezomib has also shown encouraging results in the treatment of select types of non-Hodgkin lymphomas (NHLs). Ongoing phase II clinical trials in pretreated patients are exploring bortezomib in different histologies of NHLs and in combination with conventional chemotherapy. Preliminary data have shown interesting activity, especially in patients with follicular, marginal zone, and mantle cell lymphoma; in these populations, durable complete and partial remissions have been reported. The toxicity profile of this drug, coupled with its unusual mechanism of action, make it a potentially important agent warranting further preclinical and clinical attention. However, many unanswered questions remain regarding how best to employ bortezomib in the conventional treatment of lymphoma. The apparent lack of activity in different subtypes of lymphoma, such as small lymphocytic lymphoma/chronic lymphocytic leukemia and diffuse large B-cell lymphoma, as well as a lack of understanding about the best way to combine bortezomib with standard therapies for indolent NHLs, raises important questions regarding the mechanistic basis for its effects. We will undoubtedly need to understand these effects better in order to fully exploit the potential of this new class of drugs.
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PMID:Mechanistic rationale and clinical evidence for the efficacy of proteasome inhibitors against indolent and mantle cell lymphomas. 1657 48

The ubiquitin-proteasome pathway plays a critical role in the regulated degradation of proteins involved in cell cycle control and tumor growth. Bortezomib (Velcade, formerly known as PS-341) is a potent proteasome inhibitor. In preclinical studies, bortezomib has demonstrated activity against a variety of B-cell malignancies by inducing apoptosis and sensitizing tumor cells to radiation or chemotherapy. Based on these findings, clinical trials have been conducted with bortezomib in B-cell non-Hodgkin's lymphoma. In these studies, bortezomib was generally well tolerated with manageable toxicities and showed promising clinical activity. Mantle cell lymphoma was significantly more sensitive to bortezomib than other non-Hodgkin's lymphomas. Bortezomib may have far-reaching potential in the treatment of B-cell non-Hodgkin's lymphoma.
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PMID:Use of bortezomib in B-cell non-Hodgkin's lymphoma. 1683 Oct 71

Mounting evidence suggests that dynamic interactions between a tumor and its microenvironment play a critical role in tumor development, cell-cycle progression, and response to therapy. In this study, we used mantle cell lymphoma (MCL) as a model to characterize the mechanisms by which stroma regulate cell-cycle progression. We demonstrated that adhesion of MCL and other non-Hodgkin lymphoma (NHL) cells to bone marrow stromal cells resulted in a reversible G(1) arrest associated with elevated p27(Kip1) and p21 (WAF1) proteins. The adhesion-mediated p27(Kip1) and p21 increases were posttranslationally regulated via the down-regulation of Skp2, a subunit of SCF(Skp2) ubiquitin ligase. Overexpression of Skp2 in MCL decreased p27(Kip1), whereas inhibition of Skp2 by siRNA increased p27(Kip1) and p21 levels. Furthermore, we found cell adhesion up-regulated Cdh1 (an activating subunit of anaphase-promoting complex [APC] ubiquitin ligase), and reduction of Cdh1 by siRNA induced Skp2 accumulation and hence p27(Kip1) degradation, thus implicating Cdh1 as an upstream effector of the Skp2/p27(Kip1) signaling pathway. Overall, this report, for the first time, demonstrates that cell-cell contact controls the tumor cell cycle via ubiquitin-proteasome proteolytic pathways in MCL and other NHLs. The understanding of this novel molecular pathway may prove valuable in designing new therapeutic approaches for modifying tumor cell growth and response to therapy.
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PMID:Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. 1750 56

Epstein-Barr virus (EBV) is a ubiquitous virus with infections commonly resulting in a latency carrier state. Although the exact role of EBV in cancer pathogenesis remains not entirely clear, it is highly probable that it causes several lymphoid and epithelial malignancies, such as Hodgkin's lymphoma, NK-T cell lymphoma, Burkitt's lymphoma, and nasopharyngeal carcinoma. EBV-associated malignancies are associated with a latent form of infection, and several of these EBV-encoded latent proteins are known to mediate cellular transformation. These include six nuclear antigens and three latent membrane proteins. Studies have shown that EBV displays distinct patterns of viral latent gene expression in these lymphoid and epithelial tumors. The constant expression of latent membrane protein 2A (LMP2A) at the RNA level in both primary and metastatic tumors suggests that this protein might be a driving factor in the tumorigenesis of EBV-associated malignancies. LMP2A may cooperate with the aberrant host genome, and thereby contribute to malignant transformation by intervening in signaling pathways at multiple points, especially in the cell cycle and apoptotic pathway. This review summarizes the role of EBV-encoded LMP2A in EBV-associated viral latency and cancers. We will focus our discussions on the molecular interactions of each of the conserved motifs in LMP2A, and their involvement in various signaling pathways, namely the B-cell receptor blockade mechanism, the ubiquitin-mediated (Notch and Wnt) pathways, and the MAPK, PI3-K/Akt, NK-kappaB and STAT pathways, which can provide us with important insights into the roles of LMP2A in the EBV-associated latency state and various malignancies.
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PMID:The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer. 1908 21


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