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Andrei L. Gartel - One of the best experts on this subject based on the ideXlab platform.
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Proteasome Inhibitors suppress the protein expression of mutant p53.
Cell cycle (Georgetown Tex.), 2014Co-Authors: Marianna Halasi, Bulbul Pandit, Andrei L. GartelAbstract:Tumor suppressor p53 is one of the most frequently mutated genes in cancer, with almost 50% of all types of cancer expressing a mutant form of p53. p53 transactivates the expression of its primary negative regulator, HDM2. HDM2 is a ubiquitin ligase, which initiates the proteasomal degradation of p53 following ubiquitination. Proteasome Inhibitors, by targeting the ubiquitin Proteasome pathway inhibit the degradation of the majority of cellular proteins including wild-type p53. In contrast, in this study we found that the protein expression of mutant p53 was suppressed following treatment with established or novel Proteasome Inhibitors. Furthermore, for the first time we demonstrated that Arsenic trioxide, which was previously shown to suppress mutant p53 protein level, exhibits Proteasome inhibitory activity. Proteasome inhibitor-mediated suppression of mutant p53 was partially rescued by the knockdown of HDM2, suggesting that the stabilization of HDM2 by Proteasome Inhibitors might be responsible for mutant p53 suppression to some extent. This study suggests that suppression of mutant p53 is a general property of Proteasome Inhibitors and it provides additional rationale to use Proteasome Inhibitors for the treatment of tumors with mutant p53.
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ros inhibitor n acetyl l cysteine antagonizes the activity of Proteasome Inhibitors
Biochemical Journal, 2013Co-Authors: Marianna Halasi, Ming Wang, Tanmay S Chavan, Vadim Gaponenko, Nissim Hay, Andrei L. GartelAbstract:NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of Proteasome Inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to Proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and Proteasome Inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of Proteasome Inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a Proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to Proteasome Inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of Proteasome Inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.
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Paradoxical inhibition of cellular protein expression by Proteasome Inhibitors
Biomolecular concepts, 2012Co-Authors: Andrei L. GartelAbstract:Abstract Proteasome Inhibitors are used as anticancer drugs, however, the precise mechanisms of their selective activity against cancer cells are not understood well. While Proteasome Inhibitors stabilize the majority of cellular proteins through inhibition of Proteasome activity, they also paradoxically downregulate several other proteins. We recently discovered that Proteasome Inhibitors suppress mRNA and protein expression of FOXM1, NPM, and ARF proteins that are involved in cancer. We postulated that Proteasome Inhibitors preferentially stabilize negative regulators of transcription of these genes, which overrides their protein stabilization. These data suggest a presence of multiple secondary mechanisms that may regulate transcription, degradation, or localization of cellular proteins after treatment with Proteasome Inhibitors. Future experiments will identify these mechanisms and additional proteins suppressed by Proteasome Inhibitors, and will help explain the role of protein suppression by Proteasome Inhibitors in their anticancer activity.
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Proteasome Inhibitors suppress expression of NPM and ARF proteins.
Cell cycle (Georgetown Tex.), 2011Co-Authors: Bulbul Pandit, Andrei L. GartelAbstract:Proteasome Inhibitors stabilize numerous proteins by inhibiting their degradation. Previously we have demonstrated that Proteasome Inhibitors thiostrepton, MG132 and bortezomib paradoxically inhibit transcriptional activity and mRNA/protein expression of FOXM1. Here we demonstrate that, in addition to FOXM1, the same Proteasome Inhibitors also decrease mRNA and protein expression of NPM and ARF genes. These data suggest that Proteasome Inhibitors may suppress gene expression by stabilizing their transcriptional Inhibitors.
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Proteasome Inhibitors Induce p53-Independent Apoptosis in Human Cancer Cells
The American journal of pathology, 2010Co-Authors: Bulbul Pandit, Andrei L. GartelAbstract:Proteasome Inhibitors are used against human cancer, but their mechanisms of action are not entirely understood. For example, the role of the tumor suppressor p53 is controversial. We reevaluated the role of p53 in Proteasome inhibitor-induced apoptosis by using isogenic human cancer cell lines with different p53 status. We found that well-known Proteasome Inhibitors such as MG132 and bortezomib, as well as the recently discovered Proteasome inhibitor thiostrepton, induced p53-independent apoptosis in human cancer cell lines that correlated with p53-independent induction of proapoptotic Noxa but not Puma protein. In addition, these drugs inhibited growth of several cancer cell lines independently of p53 status. Notably, thiostrepton induced more potent apoptosis in HepG2 cells with p53 knockdown than in parental cells with wild-type p53. Our data confirm that Proteasome Inhibitors generally induce p53-independent apoptosis in human cancer cells.
Craig M Crews - One of the best experts on this subject based on the ideXlab platform.
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Development and Characterization of Proteasome Inhibitors
Methods in enzymology, 2005Co-Authors: Kyung Bo Kim, Fabiana N. Fonseca, Craig M CrewsAbstract:Although many Proteasome Inhibitors have been either synthesized or identified from natural sources, the development of more sophisticated, selective Proteasome Inhibitors is important for a detailed understanding of Proteasome function. We have found that antitumor natural product epoxomicin and eponemycin, both of which are linear peptides containing a alpha,beta-epoxyketone pharmacophore, target Proteasome for their antitumor activity. Structural studies of the Proteasome-epoxomicin complex revealed that the unique specificity of the natural product toward Proteasome is due to the alpha,beta-epoxyketone pharmacophore, which forms an unusual six-membered morpholino ring with the amino terminal catalytic Thr-1 of the 20S Proteasome. Thus, we believe that a facile synthetic approach for alpha,beta-epoxyketone linear peptides provides a unique opportunity to develop Proteasome Inhibitors with novel activities. In this chapter, we discuss the detailed synthetic procedure of the alpha',beta'-epoxyketone natural product epoxomicin and its derivatives.
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Natural Product and Synthetic Proteasome Inhibitors
Proteasome Inhibitors in Cancer Therapy, 2004Co-Authors: Kyung B. Kim, Craig M CrewsAbstract:The ubiquitin—Proteasome pathway has emerged as a major player in regulation several important signaling processes such as cell proliferation and inflammation. As a result, Proteasome Inhibitors are being intensely pursued as both molecular probes of Proteasome biology and as therapeutic agents. Thus far, many Proteasome Inhibitors have been synthesized or isolated from natural sources, some of which are in clinical trial for cancer therapy. In this chapter, we discuss recent developments of both natural and synthetic Proteasome Inhibitors. Particular attention is focused on comparisons of the kinetic and/or biologic data for various Proteasome Inhibitors. Finally, we describe the design of novel Proteasome Inhibitors that target specific subunits of the Proteasome.
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the ubiquitin Proteasome pathway and Proteasome Inhibitors
Medicinal Research Reviews, 2001Co-Authors: Jayhyuk Myung, Kyung Bo Kim, Craig M CrewsAbstract:The ubiquitin-Proteasome pathway has emerged as a central player in the regulation of several diverse cellular processes. Here, we describe the important components of this complex biochemical machinery as well as several important cellular substrates targeted by this pathway and examples of human diseases resulting from defects in various components of the ubiquitin-Proteasome pathway. In addition, this review covers the chemistry of synthetic and natural Proteasome Inhibitors, emphasizing their mode of actions toward the 20S Proteasome. Given the importance of Proteasome-mediated protein degradation in various intracellular processes, Inhibitors of this pathway will continue to serve as both molecular probes of major cellular networks as well as potential therapeutic agents for various human diseases.
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Towards subunit-specific Proteasome Inhibitors: Synthesis and evaluation of peptide α',β'-epoxyketones
Chemistry and Biology, 1999Co-Authors: Mikael Elofsson, Ute Splittgerber, Royce Mohan, Jayhyuk Myung, Craig M CrewsAbstract:Background: The Proteasome is a large multicatalytic protease complex (700 kDa) involved in a number of highly regulated processes. It has three major catalytic activities: a chymotrypsin-like activity, a trypsin-like activity and a post-glutamyl peptide hydrolyzing (PGPH) activity. To be useful as molecular probes, which could help dissect the cellular functions of the Proteasome, Inhibitors should be specific for the Proteasome, active in vivo and selectively block only one of the three catalytic activities. To date, few Inhibitors fulfill these requirements so we set out to make novel Proteasome Inhibitors that incorporate these characteristics. Results: A panel of amino-terminally acetylated peptide α',β'-epoxyketones with leucine in P1 and various aliphatic or aromatic amino acids in P2-P4 were prepared and evaluated. Most compounds selectively inhibited the chymotrypsin-like activity, while only weakly inhibiting the trypsin-like and PGPH activities. After optimization, one inhibitor, Ac-hFLFL-epoxide, was found to be more potent and selective for the inhibition of the chymotrypsin-like activity than several previously described Inhibitors. This inhibitor also exhibited strong in vivo anti-inflammatory activity. Conclusions: Optimization of amino-terminally acetylated peptide α',β'-epoxyketones furnished a potent Proteasome inhibitor, Ac-hFLFL-epoxide, that has an excellent selectivity for the chymotrypsin-like activity. The inhibitor also proved to be a potent antiproliferative and anti-inflammatory agent. The strong in vivo and in vitro activities suggest that this class of Proteasome Inhibitors could be both molecular probes and therapeutic agents.
Robert Z. Orlowski - One of the best experts on this subject based on the ideXlab platform.
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Proteasome Inhibitors in cancer therapy
Nature Reviews Clinical Oncology, 2017Co-Authors: Elisabet E. Manasanch, Robert Z. OrlowskiAbstract:By preventing the accumulation of misfolded or damaged proteins, the ubiquitin-Proteasome pathway has essential functions in cell homeostasis. Cancer cells produce proteins that promote cell survival and proliferation, and inhibit cell death, and thus, clinical trials have tested the therapeutic effect of Proteasome Inhibitors on patients with a variety of cancer types, mainly haematological malignancies. Herein, the authors discuss the advances and challenges derived from the introduction of Proteasome Inhibitors in the clinic, including therapeutic resistance. The ubiquitin Proteasome pathway was discovered in the 1980s to be a central component of the cellular protein-degradation machinery with essential functions in homeostasis, which include preventing the accumulation of misfolded or deleterious proteins. Cancer cells produce proteins that promote both cell survival and proliferation, and/or inhibit mechanisms of cell death. This notion set the stage for preclinical testing of Proteasome Inhibitors as a means to shift this fine equilibrium towards cell death. Since the late 1990s, clinical trials have been conducted for a variety of malignancies, leading to regulatory approvals of Proteasome Inhibitors to treat multiple myeloma and mantle-cell lymphoma. First-generation and second-generation Proteasome Inhibitors can elicit deep initial responses in patients with myeloma, for whom these drugs have dramatically improved outcomes, but relapses are frequent and acquired resistance to treatment eventually emerges. In addition, promising preclinical data obtained with Proteasome Inhibitors in models of solid tumours have not been confirmed in the clinic, indicating the importance of primary resistance. Investigation of the mechanisms of resistance is, therefore, essential to further maximize the utility of this class of drugs in the era of personalized medicine. Herein, we discuss the advances and challenges resulting from the introduction of Proteasome Inhibitors into the clinic. The Proteasome is a central component of the protein degradation machinery in eukaryotic cells Both transformed and normal cells depend on the function of the Proteasome to control the expression of proteins linked to cell survival and proliferation Clinical trials using Proteasome Inhibitors in myeloma, mantle-cell lymphoma (MCL) and amyloidosis have transformed the treatment of these diseases by establishing new standards of care Three Proteasome Inhibitors have received regulatory approval and are used routinely in clinical settings, including bortezomib, carfilzomib and ixazomib Primary resistance to Proteasome Inhibitors remains a challenge in patients with solid tumours; in addition, acquired resistance can be developed in myeloma and MCL even after initial responses, through mechanisms that are beginning to be understood Clinical evaluation of compounds targeting the upstream regulatory components of the Proteasome is underway; in the future, compounds that target Proteasome-mediated degradation of specific proteins might also become available
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Proteasome Inhibitors in cancer therapy
Nature reviews. Clinical oncology, 2017Co-Authors: Elisabet E. Manasanch, Robert Z. OrlowskiAbstract:The ubiquitin Proteasome pathway was discovered in the 1980s to be a central component of the cellular protein-degradation machinery with essential functions in homeostasis, which include preventing the accumulation of misfolded or deleterious proteins. Cancer cells produce proteins that promote both cell survival and proliferation, and/or inhibit mechanisms of cell death. This notion set the stage for preclinical testing of Proteasome Inhibitors as a means to shift this fine equilibrium towards cell death. Since the late 1990s, clinical trials have been conducted for a variety of malignancies, leading to regulatory approvals of Proteasome Inhibitors to treat multiple myeloma and mantle-cell lymphoma. First-generation and second-generation Proteasome Inhibitors can elicit deep initial responses in patients with myeloma, for whom these drugs have dramatically improved outcomes, but relapses are frequent and acquired resistance to treatment eventually emerges. In addition, promising preclinical data obtained with Proteasome Inhibitors in models of solid tumours have not been confirmed in the clinic, indicating the importance of primary resistance. Investigation of the mechanisms of resistance is, therefore, essential to further maximize the utility of this class of drugs in the era of personalized medicine. Herein, we discuss the advances and challenges resulting from the introduction of Proteasome Inhibitors into the clinic.
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Novel Proteasome Inhibitors
Advances in Biology and Therapy of Multiple Myeloma, 2012Co-Authors: Robert Z. OrlowskiAbstract:Proteasome inhibition is a rational approach to the therapy of multiple myeloma both alone and in combination with other agents, where Proteasome Inhibitors help induce chemosensitization and overcome drug resistance. These concepts were initially validated with laboratory-grade Proteasome Inhibitors and then with the clinically relevant peptide boronic acid bortezomib. A second generation of Proteasome Inhibitors is now being evaluated both preclinically and clinically, including carfilzomib, CEP-18770, marizomib, and MLN9708, among others. Though all of these agents target predominantly the chymotrypsin-like activity of the Proteasome expressed by the β5 subunit, they also have novel and unique properties, including different chemistries, pharmacokinetics, Proteasome binding characteristics, and other Proteasome subunit specificities. Characterization of these agents has provided a strong rationale for their translation into the clinic, and initial studies suggest that at least several of them could become part of our future chemotherapeutic armamentarium against myeloma. In this chapter, these various properties of the so-called second-generation Proteasome Inhibitors will be examined, and the biological and clinical basis of their potential will be reviewed.
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Proteasome Inhibitors in the treatment of multiple myeloma.
Leukemia, 2009Co-Authors: Jatin J. Shah, Robert Z. OrlowskiAbstract:Targeting intracellular protein turnover by inhibiting the ubiquitin-Proteasome pathway as a strategy for cancer therapy is a new addition to our chemotherapeutic armamentarium, and has seen its greatest successes against multiple myeloma. The first-in-class Proteasome inhibitor, bortezomib, was initially approved for treatment of patients in the relapsed/refractory setting as a single agent, and was recently shown to induce even greater benefits as part of rationally designed combinations that overcome chemoresistance. Modulation of Proteasome function is also a rational approach to achieve chemosensitization to other antimyeloma agents, and bortezomib has now been incorporated into the front-line setting. Bortezomib-based induction regimens are able to achieve higher overall response rates and response qualities than was the case with prior standards of care, and unlike these older approaches, maintain efficacy in patients with clinically and molecularly defined high-risk disease. Second-generation Proteasome Inhibitors with novel properties, such as NPI-0052 and carfilzomib, are entering the clinical arena, and showing evidence of antimyeloma activity. In this spotlight review, we provide an overview of the current state of the art use of bortezomib and other Proteasome Inhibitors against multiple myeloma, and highlight areas for future study that will further optimize our ability to benefit patients with this disease.
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Proteasome Inhibitors in cancer therapy lessons from the first decade
Clinical Cancer Research, 2008Co-Authors: Robert Z. Orlowski, Deborah J KuhnAbstract:The ubiquitin-Proteasome pathway is involved in intracellular protein turnover, and its function is crucial to cellular homeostasis. First synthesized as probes of proteolytic processes, Proteasome Inhibitors began to be thought of as potential drug candidates when they were found to induce programmed cell death preferentially in transformed cells. They made their first leap into the clinic to be tested as therapeutic agents 10 years ago, and since then, great strides have been made in defining their mechanisms of action, their clinical efficacy and toxicity, and some of their limitations in the form of resistance pathways. Validation of the ubiquitin-Proteasome pathway as a target for cancer therapy has come in the form of approvals of the first such inhibitor, bortezomib, for relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this agent has become a standard of care. Lessons learned from this first-in-class agent are now being applied to the development of a new generation of Proteasome Inhibitors that hold the promise of efficacy in bortezomib-resistant disease and possibly in a broader spectrum of diseases. This saga provides a salient example of the promise of translational medicine and a paradigm by which other agents may be successfully brought from the bench to the bedside.
Paul G. Richardson - One of the best experts on this subject based on the ideXlab platform.
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The Proteasome and Proteasome Inhibitors in multiple myeloma
Cancer metastasis reviews, 2017Co-Authors: Sara Gandolfi, Kenneth C. Anderson, Teru Hideshima, Dharminder Chauhan, Jacob P. Laubach, Paul G. RichardsonAbstract:Proteasome Inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration—the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral Proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S Proteasome, which plays a critical role in the pathogenesis and proliferation of the disease. Proteasome inhibition results in multiple downstream effects, including the inhibition of NF-κB signaling, the accumulation of misfolded and unfolded proteins, resulting in endoplasmic reticulum stress and leading to the unfolded protein response, the downregulation of growth factor receptors, suppression of adhesion molecule expression, and inhibition of angiogenesis; resistance to Proteasome inhibition may arise through cellular responses mediating these downstream effects. These multiple biologic consequences of Proteasome inhibition result in synergistic or additive activity with other chemotherapeutic and targeted agents for myeloma, and Proteasome inhibitor-based combination regimens have become established as a cornerstone of therapy throughout the myeloma treatment algorithm, incorporating agents from the other key classes of antimyeloma agents, including the immunomodulatory drugs, monoclonal antibodies, and histone deacetylase Inhibitors. This review gives an overview of the critical role of the Proteasome in myeloma and the characteristics of the different Proteasome Inhibitors and provides a comprehensive summary of key clinical efficacy and safety data with the currently approved Proteasome Inhibitors.
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Resistance to Proteasome Inhibitors in Multiple Myeloma
Resistance to Targeted Anti-Cancer Therapeutics, 2014Co-Authors: Francesca Cottini, Kenneth C. Anderson, Teru Hideshima, Anna Guidetti, Claudia Paba Prada, Michelle E. Maglio, Cindy Varga, Dharminder Chauhan, Jacob P. Laubach, Paul G. RichardsonAbstract:Multiple myeloma (MM) is a clonal proliferation of malignant plasma cells in the bone marrow associated with a spectrum of clinical symptoms including bone destruction, anemia, hypercalcemia, and renal failure. Although MM remains incurable, a dramatic paradigm shift in the treatment of MM has occurred over the past decade through the introduction of novel agents, including the development of small molecule Inhibitors targeting the Proteasome. Among the Proteasome Inhibitors (PIs), bortezomib (BTZ) and carfilzomib (CFZ) have been approved by the FDA for treatment of relapsed/refractory MM in 2003 and 2012, respectively. Recently, other PIs, such as ixazomib (MLN-9708), oprozomib (ONX0912), and marizomib (NPI-0052), have been under evaluation in preclinical and clinical studies. Indeed, it is now well known that malignant plasma cells are exquisitely sensitive to Proteasome Inhibitors due to protein overload and ER stress. Unfortunately, relapse of myeloma develops due to acquisition of resistance to Proteasome Inhibitors. Specifically, mutations in overexpression of proteins belonging to the Proteasome complex, upregulation of transporter channels or cytochrome components, induction of alternative compensative mechanisms such as the aggresome pathway, and modulation of downstream pathways have been all reported as possible mechanisms of Proteasome inhibitor resistance. In this chapter, we will first briefly describe the structure and function of the Proteasome in normal and malignant plasma cells, and then define the major mechanisms of resistance to Proteasome inhibition, and clinical approaches to overcoming these pathways in the context of both clinical application of PIs and rational combinations of them with other agents in the treatment of MM.
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New Proteasome Inhibitors in Myeloma
Current Hematologic Malignancy Reports, 2012Co-Authors: Panisinee Lawasut, Kenneth C. Anderson, Constantine S. Mitsiades, Teru Hideshima, Michelle E. Maglio, Dharminder Chauhan, Jacob Laubach, Catriona Hayes, Claire Fabre, Paul G. RichardsonAbstract:Proteasome inhibition has a validated role in cancer therapy since the successful introduction of bortezomib for the treatment of multiple myeloma (MM) and mantle cell lymphoma, leading to the development of second-generation Proteasome Inhibitors (PI) for MM patients in whom currently approved therapies have failed. Five PIs have reached clinical evaluation, with the goals of improving efficacy and limiting toxicity, including peripheral neuropathy (PN). Carfilzomib, an epoxyketone with specific chymothrypsin-like activity, acts as an irreversible inhibitor and was recently FDA approved for the response benefit seen in relapsed and refractory MM patients previously treated with bortezomib, thalidomide and lenalidomide. ONX-0912 is now under evaluation as an oral form with similar activity. The boronate peptides MLN9708 and CEP-18770 are orally bioactive bortezomib analogs with prolonged activity and greater tissue penetration. NPI-0052 (marizomib) is a unique, beta-lactone non-selective PI that has been shown to potently overcome bortezomib resistance in vitro. All of these second-generation PIs demonstrate encouraging anti-MM activity and appear to reduce the incidence of PN, with clinical trials ongoing.
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Proteasome Inhibitors as therapeutics.
Essays in biochemistry, 2005Co-Authors: Constantine S. Mitsiades, Nicholas Mitsiades, Teru Hideshima, Paul G. Richardson, Kenneth C. AndersonAbstract: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-Hodgkin9s lymphomas.
Kenneth C. Anderson - One of the best experts on this subject based on the ideXlab platform.
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The Proteasome and Proteasome Inhibitors in multiple myeloma
Cancer metastasis reviews, 2017Co-Authors: Sara Gandolfi, Kenneth C. Anderson, Teru Hideshima, Dharminder Chauhan, Jacob P. Laubach, Paul G. RichardsonAbstract:Proteasome Inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration—the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral Proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S Proteasome, which plays a critical role in the pathogenesis and proliferation of the disease. Proteasome inhibition results in multiple downstream effects, including the inhibition of NF-κB signaling, the accumulation of misfolded and unfolded proteins, resulting in endoplasmic reticulum stress and leading to the unfolded protein response, the downregulation of growth factor receptors, suppression of adhesion molecule expression, and inhibition of angiogenesis; resistance to Proteasome inhibition may arise through cellular responses mediating these downstream effects. These multiple biologic consequences of Proteasome inhibition result in synergistic or additive activity with other chemotherapeutic and targeted agents for myeloma, and Proteasome inhibitor-based combination regimens have become established as a cornerstone of therapy throughout the myeloma treatment algorithm, incorporating agents from the other key classes of antimyeloma agents, including the immunomodulatory drugs, monoclonal antibodies, and histone deacetylase Inhibitors. This review gives an overview of the critical role of the Proteasome in myeloma and the characteristics of the different Proteasome Inhibitors and provides a comprehensive summary of key clinical efficacy and safety data with the currently approved Proteasome Inhibitors.
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Resistance to Proteasome Inhibitors in Multiple Myeloma
Resistance to Targeted Anti-Cancer Therapeutics, 2014Co-Authors: Francesca Cottini, Kenneth C. Anderson, Teru Hideshima, Anna Guidetti, Claudia Paba Prada, Michelle E. Maglio, Cindy Varga, Dharminder Chauhan, Jacob P. Laubach, Paul G. RichardsonAbstract:Multiple myeloma (MM) is a clonal proliferation of malignant plasma cells in the bone marrow associated with a spectrum of clinical symptoms including bone destruction, anemia, hypercalcemia, and renal failure. Although MM remains incurable, a dramatic paradigm shift in the treatment of MM has occurred over the past decade through the introduction of novel agents, including the development of small molecule Inhibitors targeting the Proteasome. Among the Proteasome Inhibitors (PIs), bortezomib (BTZ) and carfilzomib (CFZ) have been approved by the FDA for treatment of relapsed/refractory MM in 2003 and 2012, respectively. Recently, other PIs, such as ixazomib (MLN-9708), oprozomib (ONX0912), and marizomib (NPI-0052), have been under evaluation in preclinical and clinical studies. Indeed, it is now well known that malignant plasma cells are exquisitely sensitive to Proteasome Inhibitors due to protein overload and ER stress. Unfortunately, relapse of myeloma develops due to acquisition of resistance to Proteasome Inhibitors. Specifically, mutations in overexpression of proteins belonging to the Proteasome complex, upregulation of transporter channels or cytochrome components, induction of alternative compensative mechanisms such as the aggresome pathway, and modulation of downstream pathways have been all reported as possible mechanisms of Proteasome inhibitor resistance. In this chapter, we will first briefly describe the structure and function of the Proteasome in normal and malignant plasma cells, and then define the major mechanisms of resistance to Proteasome inhibition, and clinical approaches to overcoming these pathways in the context of both clinical application of PIs and rational combinations of them with other agents in the treatment of MM.
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New Proteasome Inhibitors in Myeloma
Current Hematologic Malignancy Reports, 2012Co-Authors: Panisinee Lawasut, Kenneth C. Anderson, Constantine S. Mitsiades, Teru Hideshima, Michelle E. Maglio, Dharminder Chauhan, Jacob Laubach, Catriona Hayes, Claire Fabre, Paul G. RichardsonAbstract:Proteasome inhibition has a validated role in cancer therapy since the successful introduction of bortezomib for the treatment of multiple myeloma (MM) and mantle cell lymphoma, leading to the development of second-generation Proteasome Inhibitors (PI) for MM patients in whom currently approved therapies have failed. Five PIs have reached clinical evaluation, with the goals of improving efficacy and limiting toxicity, including peripheral neuropathy (PN). Carfilzomib, an epoxyketone with specific chymothrypsin-like activity, acts as an irreversible inhibitor and was recently FDA approved for the response benefit seen in relapsed and refractory MM patients previously treated with bortezomib, thalidomide and lenalidomide. ONX-0912 is now under evaluation as an oral form with similar activity. The boronate peptides MLN9708 and CEP-18770 are orally bioactive bortezomib analogs with prolonged activity and greater tissue penetration. NPI-0052 (marizomib) is a unique, beta-lactone non-selective PI that has been shown to potently overcome bortezomib resistance in vitro. All of these second-generation PIs demonstrate encouraging anti-MM activity and appear to reduce the incidence of PN, with clinical trials ongoing.
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Second-Generation Proteasome Inhibitors
Bortezomib in the Treatment of Multiple Myeloma, 2010Co-Authors: Dixie-lee Esseltine, Mark Williamson, Larry Dick, Erik Kupperman, Kenneth C. AndersonAbstract:The first-in-class Proteasome inhibitor, bortezomib, has provided proof-of-concept for the therapeutic approach of Proteasome inhibition in a number of malignancies. However, as we look to the future and to further improving upon the contributions of this class of drugs, we will need to consider optimizing activity in solid tumors, reducing peripheral neuropathy and utilizing more convenient routes of administration. A number of “second-generation” Proteasome Inhibitors have been identified and are now in preclinical and clinical development, including MLN9708, CEP-18770, carfilzomib, and salinosporamide A (NPI-0052). These agents differ from bortezomib in some of their key characteristics, and differences in their pharmacology may result in different activity and safety profiles. This chapter reviews the second-generation Proteasome Inhibitors, together with other potential therapeutic targets in the ubiquitin–Proteasome system.
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Proteasome Inhibitors as therapeutics.
Essays in biochemistry, 2005Co-Authors: Constantine S. Mitsiades, Nicholas Mitsiades, Teru Hideshima, Paul G. Richardson, Kenneth C. AndersonAbstract: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-Hodgkin9s lymphomas.
