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Title: Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance
Authors: Leonardo-Sousa, Carlota
Carvalho, Andreia Neves
Guedes, Romina A. 
Fernandes, Pedro M. P. 
Aniceto, Natália
Salvador, Jorge A. R. 
Gama, Maria João
Guedes, Rita C. 
Keywords: ubiquitin–proteasome pathway; proteasome inhibitors; mechanisms of resistance; innate resistance; acquired resistance; multiple myeloma; cancer
Issue Date: 28-Mar-2022
Publisher: MDPI
Project: PD/BD/145161/2019 
Serial title, monograph or event: Molecules
Volume: 27
Issue: 7
Abstract: Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity-a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance.
ISSN: 1420-3049
DOI: 10.3390/molecules27072201
Rights: openAccess
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais

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