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Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?
Linkoping Univ, Dept Med & Hlth Sci, SE-58185 Linkoping, Sweden..
Karolinska Inst, Dept Pathol & Oncol, SE-17176 Stockholm, Sweden..
Linkoping Univ, Dept Med & Hlth Sci, SE-58185 Linkoping, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
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2015 (English)In: Drug resistance updates, ISSN 1368-7646, E-ISSN 1532-2084, Vol. 21-22, 20-29 p.Article, review/survey (Refereed) Published
Abstract [en]

Although more traditionally associated with degradation and maintenance of protein homeostasis, the ubiquitin-proteasome system (UPS) has emerged as a critical component in the regulation of cancer cell growth and survival. The development of inhibitors that block the proteolytic activities of the proteasome have highlighted its suitability as a bona fide anti-cancer drug target. However, key determinants including the development of drug resistance and dose-limiting toxicity call for the identification of alternative components of the UPS for novel drug targeting. Recently the deubiquitinases (DUBS), a diverse family of enzymes that catalyze ubiquitin removal, have attracted significant interest as targets for the development of next generation UPS inhibitors. In particular, pharmacological inhibition of the proteasomal cysteine DUBs (i.e., USP14 and UCHL5) has been shown to be particularly cytotoxic to cancer cells and inhibit tumour growth in several in vivo models. In the current review we focus on the modes of action of proteasome DUB inhibitors and discus the potential of DUB inhibitors to circumvent acquired drug resistance and provide a therapeutic option for the treatment of cancer.

Place, publisher, year, edition, pages
2015. Vol. 21-22, 20-29 p.
Keyword [en]
Cancer therapeutics, Small molecule inhibitors, Proteasome, Deubiquitinase, DUB, alpha, beta-Unsaturated ketones, Apoptosis
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-266284DOI: 10.1016/j.drup.2015.06.001ISI: 000362060500003PubMedID: 26183292OAI: oai:DiVA.org:uu-266284DiVA: diva2:867780
Funder
Swedish Cancer SocietySwedish Research CouncilSwedish Childhood Cancer Foundation
Available from: 2015-11-06 Created: 2015-11-06 Last updated: 2017-12-01Bibliographically approved

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Gullbo, Joachim

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