Molecular basis of resistance to proteasome inhibitors in hematological malignancies

Over the past decade, the proteasome inhibitor bortezomib (Velcade) has not only gained a cornerstone position in the treatment of hematological malignancies, particularly multiple myeloma and mantle cell lymphoma, but also in experimental therapeutics of acute leukemia. However, the therapeutic eff...

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Veröffentlicht in:Drug resistance updates Jg. 18; S. 18 - 35
Hauptverfasser: Niewerth, Denise, Jansen, Gerrit, Assaraf, Yehuda G., Zweegman, Sonja, Kaspers, Gertjan J.L., Cloos, Jacqueline
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Scotland Elsevier Ltd 01.01.2015
Schlagworte:
Animals
Antineoplastic Agents - adverse effects
Antineoplastic Agents - pharmacology
Boronic Acids - adverse effects
Boronic Acids - pharmacology
Bortezomib
Drug Resistance, Neoplasm
Hematologic Neoplasms - drug therapy
Hematologic Neoplasms - pathology
Hematology, Oncology and Palliative Medicine
Humans
Infectious Disease
Leukemia
Multiple myeloma
Proteasome inhibitor
Proteasome Inhibitors - pharmacology
Pyrazines - adverse effects
Pyrazines - pharmacology
Resistance
Resistance
Bortezomib
Proteasome inhibitor
Leukemia
Multiple myeloma
ISSN:1368-7646, 1532-2084, 1532-2084
Online-Zugang:Volltext
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Zusammenfassung:Over the past decade, the proteasome inhibitor bortezomib (Velcade) has not only gained a cornerstone position in the treatment of hematological malignancies, particularly multiple myeloma and mantle cell lymphoma, but also in experimental therapeutics of acute leukemia. However, the therapeutic efficacy of bortezomib is hampered by the emergence of acquired resistance, for which multifactorial mechanisms have been identified. This review summarizes the current status of the molecular mechanisms underlying resistance to proteasome inhibitors that emerged in preclinical therapeutic studies, and discusses these findings in the clinical perspective of novel therapeutic modalities of hematological malignancies. The specific topics that will be addressed in the current review include the recently established mechanisms of resistance to proteasome inhibitors: the role of constitutive and immunoproteasomes, mutations in proteasome subunits, unfolded protein response, XBP1 and MARCKS proteins, multidrug efflux transporters, aggresomes and autophagy, as well as the impact of pro-survival signaling pathways and bone marrow microenvironment. The growing knowledge of the determinants that confer bortezomib resistance and/or toxicity has provided the basis for the rational development of second generation proteasome inhibitors, some of which were recently approved or that are undergoing clinical evaluation as novel strategies to overcome bortezomib resistance as well as to enhance clinical therapeutic efficacy along with minimal side effects. Collectively, these combined approaches should enhance therapeutic efficacy and outcome in patients with hematological malignancies.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
ObjectType-Review-3
content type line 23
ISSN:1368-7646
1532-2084
1532-2084
DOI:10.1016/j.drup.2014.12.001