Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development, Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 100964009 Publication Model: Electronic Cited Medium: Internet ISSN: 1420-3049 (Electronic) Linking ISSN: 14203049 NLM ISO Abbreviation: Molecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, c1995-

Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/therapeutic use ; Multiple Myeloma*/drug therapy ; Neoplasms*/drug therapy; Adult ; Bortezomib/pharmacology ; Bortezomib/therapeutic use ; Humans ; Proteasome Endopeptidase Complex ; Proteasome Inhibitors/pharmacology ; Proteasome Inhibitors/therapeutic use ; Quality of Life

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.

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Keywords: acquired resistance; cancer; innate resistance; mechanisms of resistance; multiple myeloma; proteasome inhibitors; ubiquitin–proteasome pathway

0 (Antineoplastic Agents)
0 (Proteasome Inhibitors)
69G8BD63PP (Bortezomib)
EC 3.4.25.1 (Proteasome Endopeptidase Complex)

Date Created: 20220412 Date Completed: 20220413 Latest Revision: 20220423

20240628

PMC9000344

10.3390/molecules27072201

35408601