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The ubiquitin+proteasome protein degradation pathway as a therapeutic strategy in the treatment of solid tumor malignancies.

Abstract：

:A concept that currently steers the development of cancer therapies has been that agents directed against specific proteins that facilitate tumorigenesis or maintain a malignant phenotype will have greater efficacy, less toxicity and a more sustained response relative to traditional cytotoxic chemotherapeutic agents. The clinical success of the targeted agent Imatinib mesylate as an inhibitor of the tyrosine kinase associated with the breakpoint cluster region-Abelson oncogene locus (BCR-ABL) in the treatment of Philadelphia-positive chronic myelogenous leukemia (CML) has served as a paradigm. While intellectually gratifying, the selective targeting of a single driver event by a small molecule, e.g., kinase inhibitor, to dampen a tumor-promoting pathway in the treatment of solid tumors is limited by many factors. Focus can alternatively be placed on targeting fundamental cellular processes that regulate multiple events, e.g., protein degradation, through the Ubiquitin (Ub)+Proteasome System (UPS). The UPS plays a critical role in modulating numerous cellular proteins to regulate cellular processes such as signal transduction, growth, proliferation, differentiation and apoptosis. Clinical success with the proteasome inhibitor bortezomib revolutionized treatment of B-cell lineage malignancies such as Multiple Myeloma (MM). However, many patients harbor primary resistance and do not respond to bortezomib and those that do respond inevitably develop resistance (secondary resistance). The lack of clinical efficacy of proteasome inhibitors in the treatment of solid tumors may be linked mechanistically to the resistance detected during treatment of hematologic malignancies. Potential mechanisms of resistance and means to improve the response to proteasome inhibitors in solid tumors are discussed.

journal_name

Anticancer Agents Med Chem

journal_title

Anti-cancer agents in medicinal chemistry

authors

Driscoll JJ,Minter A,Driscoll DA,Burris JK

doi

10.2174/187152011795255948

subject

Has Abstract

pub_date

2011-02-01 00:00:00

pages

242-6

issue

eissn

1871-5206

issn

1875-5992

pii

BSP/ACAMC/E-Pub/ 00144

journal_volume

pub_type

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The ubiquitin+proteasome protein degradation pathway as a therapeutic strategy in the treatment of solid tumor malignancies.