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Trial Watch: Proteasomal inhibitors for anticancer therapy

The so-called “ubiquitin-proteasome system” (UPS) is a multicomponent molecular apparatus that catalyzes the covalent attachment of several copies of the small protein ubiquitin to other proteins that are generally (but not always) destined to proteasomal degradation. This enzymatic cascade is cruci...

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Autores principales: Obrist, Florine, Manic, Gwenola, Kroemer, Guido, Vitale, Ilio, Galluzzi, Lorenzo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904962/
https://www.ncbi.nlm.nih.gov/pubmed/27308423
http://dx.doi.org/10.4161/23723556.2014.974463
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author Obrist, Florine
Manic, Gwenola
Kroemer, Guido
Vitale, Ilio
Galluzzi, Lorenzo
author_facet Obrist, Florine
Manic, Gwenola
Kroemer, Guido
Vitale, Ilio
Galluzzi, Lorenzo
author_sort Obrist, Florine
collection PubMed
description The so-called “ubiquitin-proteasome system” (UPS) is a multicomponent molecular apparatus that catalyzes the covalent attachment of several copies of the small protein ubiquitin to other proteins that are generally (but not always) destined to proteasomal degradation. This enzymatic cascade is crucial for the maintenance of intracellular protein homeostasis (both in physiological conditions and in the course of adaptive stress responses), and regulates a wide array of signaling pathways. In line with this notion, defects in the UPS have been associated with aging as well as with several pathological conditions including cardiac, neurodegenerative, and neoplastic disorders. As transformed cells often experience a constant state of stress (as a result of the hyperactivation of oncogenic signaling pathways and/or adverse microenvironmental conditions), their survival and proliferation are highly dependent on the integrity of the UPS. This rationale has driven an intense wave of preclinical and clinical investigation culminating in 2003 with the approval of the proteasomal inhibitor bortezomib by the US Food and Drug Administration for use in multiple myeloma patients. Another proteasomal inhibitor, carfilzomib, is now licensed by international regulatory agencies for use in multiple myeloma patients, and the approved indications for bortezomib have been extended to mantle cell lymphoma. This said, the clinical activity of bortezomib and carfilzomib is often limited by off-target effects, innate/acquired resistance, and the absence of validated predictive biomarkers. Moreover, the antineoplastic activity of proteasome inhibitors against solid tumors is poor. In this Trial Watch we discuss the contribution of the UPS to oncogenesis and tumor progression and summarize the design and/or results of recent clinical studies evaluating the therapeutic profile of proteasome inhibitors in cancer patients.
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spelling pubmed-49049622016-06-15 Trial Watch: Proteasomal inhibitors for anticancer therapy Obrist, Florine Manic, Gwenola Kroemer, Guido Vitale, Ilio Galluzzi, Lorenzo Mol Cell Oncol Review The so-called “ubiquitin-proteasome system” (UPS) is a multicomponent molecular apparatus that catalyzes the covalent attachment of several copies of the small protein ubiquitin to other proteins that are generally (but not always) destined to proteasomal degradation. This enzymatic cascade is crucial for the maintenance of intracellular protein homeostasis (both in physiological conditions and in the course of adaptive stress responses), and regulates a wide array of signaling pathways. In line with this notion, defects in the UPS have been associated with aging as well as with several pathological conditions including cardiac, neurodegenerative, and neoplastic disorders. As transformed cells often experience a constant state of stress (as a result of the hyperactivation of oncogenic signaling pathways and/or adverse microenvironmental conditions), their survival and proliferation are highly dependent on the integrity of the UPS. This rationale has driven an intense wave of preclinical and clinical investigation culminating in 2003 with the approval of the proteasomal inhibitor bortezomib by the US Food and Drug Administration for use in multiple myeloma patients. Another proteasomal inhibitor, carfilzomib, is now licensed by international regulatory agencies for use in multiple myeloma patients, and the approved indications for bortezomib have been extended to mantle cell lymphoma. This said, the clinical activity of bortezomib and carfilzomib is often limited by off-target effects, innate/acquired resistance, and the absence of validated predictive biomarkers. Moreover, the antineoplastic activity of proteasome inhibitors against solid tumors is poor. In this Trial Watch we discuss the contribution of the UPS to oncogenesis and tumor progression and summarize the design and/or results of recent clinical studies evaluating the therapeutic profile of proteasome inhibitors in cancer patients. Taylor & Francis 2014-12-01 /pmc/articles/PMC4904962/ /pubmed/27308423 http://dx.doi.org/10.4161/23723556.2014.974463 Text en © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.
spellingShingle Review
Obrist, Florine
Manic, Gwenola
Kroemer, Guido
Vitale, Ilio
Galluzzi, Lorenzo
Trial Watch: Proteasomal inhibitors for anticancer therapy
title Trial Watch: Proteasomal inhibitors for anticancer therapy
title_full Trial Watch: Proteasomal inhibitors for anticancer therapy
title_fullStr Trial Watch: Proteasomal inhibitors for anticancer therapy
title_full_unstemmed Trial Watch: Proteasomal inhibitors for anticancer therapy
title_short Trial Watch: Proteasomal inhibitors for anticancer therapy
title_sort trial watch: proteasomal inhibitors for anticancer therapy
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904962/
https://www.ncbi.nlm.nih.gov/pubmed/27308423
http://dx.doi.org/10.4161/23723556.2014.974463
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