Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2006, vol. 15, nr 2, March-April, p. 309–320

Publication type: review article

Language: Polish

Zastosowanie inhibitorów proteasomów w chorobach nowotworowych

Proteasome Inhibition as a Novel Therapeutic Target in Neoplasmatic Diseases

Artur Jurczyszyn1,, Aleksander B. Skotnicki1,

1 Katedra i Klinika Hematologii CM UJ, Kraków

Streszczenie

Proteasom 26S jest dużą, wewnątrzkomórkową proteazą, rozpoznającą i degradującą białka zaznaczone przez układ ubikwityny do zniszczenia. Właściwa degradacja białek komórkowych ma znaczenie dla czynności komórek prawidłowych, a inhibicja szlaku proteasomów prowadzi do zatrzymania cyklu komórkowego i apoptozy. Zaburzenia regulacji tego układu enzymatycznego mogą również odgrywać rolę w rozwoju nowotworu i oporności na leki, co czyni inhibicję proteasomów nowym celem terapeutycznym. Bortezomib – dipeptyd kwasu boronowego, bezpośrednio inhibujący kompleks enzymatyczny, jest pierwszym inhibitorem proteasomów, który wszedł do praktyki klinicznej. Ostatnio wykazano aktywność bortezomibu w kilku typach nowotworów, co potwierdza wartość terapeutyczną hamowania proteasomów w tych chorobach u człowieka. Został zatwierdzony w 2003 r. do leczenia opornego szpiczaka mnogiego (MM), a u około jednej trzeciej pacjentów z nawrotem MM nastąpiła remisja lub stabilizacja choroby, co stwierdzono w dużych badaniach klinicznych. Mechanizm działania bortezomibu jest częściowo monitorowany przez inhibicję czynnika jądrowego−kappa B, prowadząc do apoptozy, zmniejszenia ekspresji cytokin angiogennych i hamowania przylegania komórek nowotworowych do zrębu. Obecnie trwają badania kliniczne nad zastosowaniem bortezomibu w MM i w innych nowotworach złośliwych. W artykule omówiono inhibicję proteasomów jako nowy cel terapeutyczny, skupiając się na mechanizmach działania i aktualnych doświadczeniach klinicznych z bortezomibem (Adv Clin Med 2006, 15, 2, 309–320).

Abstract

The 26S proteasome is a large intracellular protease that identifies and degrades proteins tagged for destruction by the ubiquitin system. The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell−cycle arrest and apoptosis. Dysregulation of this enzymatic system may also play a role in tumor progression, drug resistance, and altered immune surveillance, making the proteasome an appropriate and novel therapeutic target in cancer. Bortezomib is the first proteasome inhibitor to enter clinical practice. It is a boronic aid dipeptide that binds directly with and inhibits the enzymatic complex. Bortezomib has recently shown significant preclinical and clinical activity in several cancers, confirming the therapeutic value of proteasome inhibition in human malignancy. It was approved in 2003 for the treatment of advanced multiple myeloma (MM), with approximately one third of patients with relapsed and refractory MM showing significant clinical benefit in a large clinical trial. Its mechanism of action is partly mediated through nuclear factorkappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Several clinical trials are currently ongoing in MM as well as several other malignancies. This article discusses proteasome inhibition as a novel therapeutic target in cancer and focuses on the development, mechanism of action, and current clinical experience with bortezomib (Adv Clin Med 2006, 15, 2, 309–320).

Słowa kluczowe

inhibicja proteasomów, bortezomib, szpiczak mnogi, NF−κB

Key words

proteasome inhibition, bortezomib, multiple myeloma, NF−κB

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