Proteasome inhibition as a novel therapeutic target in human cancer

S Vincent Rajkumar, Paul G. Richardson, Teru Hideshima, Kenneth C. Anderson

Research output: Contribution to journalArticle

481 Citations (Scopus)

Abstract

The 26S proteasome is a large intracellular adenosine 5′- triphosphate-dependent 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 (formerly known as PS-341) 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 factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. 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.

Original languageEnglish (US)
Pages (from-to)630-639
Number of pages10
JournalJournal of Clinical Oncology
Volume23
Issue number3
DOIs
StatePublished - 2005

Fingerprint

Proteasome Endopeptidase Complex
Multiple Myeloma
Neoplasms
Therapeutics
Clinical Trials
Apoptosis
Proteasome Inhibitors
JNK Mitogen-Activated Protein Kinases
NF-kappa B
Dipeptides
Ubiquitin
Cell Cycle Checkpoints
Drug Resistance
Cell Adhesion
Proteolysis
Intercellular Signaling Peptides and Proteins
Peptide Hydrolases
Adenosine Triphosphate
Cytokines
Bortezomib

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Proteasome inhibition as a novel therapeutic target in human cancer. / Rajkumar, S Vincent; Richardson, Paul G.; Hideshima, Teru; Anderson, Kenneth C.

In: Journal of Clinical Oncology, Vol. 23, No. 3, 2005, p. 630-639.

Research output: Contribution to journalArticle

Rajkumar, S Vincent ; Richardson, Paul G. ; Hideshima, Teru ; Anderson, Kenneth C. / Proteasome inhibition as a novel therapeutic target in human cancer. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 3. pp. 630-639.
@article{ccebb9ca422a4cb9bf68a499537c7510,
title = "Proteasome inhibition as a novel therapeutic target in human cancer",
abstract = "The 26S proteasome is a large intracellular adenosine 5′- triphosphate-dependent 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 (formerly known as PS-341) 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 factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. 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.",
author = "Rajkumar, {S Vincent} and Richardson, {Paul G.} and Teru Hideshima and Anderson, {Kenneth C.}",
year = "2005",
doi = "10.1200/JCO.2005.11.030",
language = "English (US)",
volume = "23",
pages = "630--639",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "3",

}

TY - JOUR

T1 - Proteasome inhibition as a novel therapeutic target in human cancer

AU - Rajkumar, S Vincent

AU - Richardson, Paul G.

AU - Hideshima, Teru

AU - Anderson, Kenneth C.

PY - 2005

Y1 - 2005

N2 - The 26S proteasome is a large intracellular adenosine 5′- triphosphate-dependent 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 (formerly known as PS-341) 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 factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. 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.

AB - The 26S proteasome is a large intracellular adenosine 5′- triphosphate-dependent 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 (formerly known as PS-341) 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 factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. 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.

UR - http://www.scopus.com/inward/record.url?scp=14544303662&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=14544303662&partnerID=8YFLogxK

U2 - 10.1200/JCO.2005.11.030

DO - 10.1200/JCO.2005.11.030

M3 - Article

C2 - 15659509

AN - SCOPUS:14544303662

VL - 23

SP - 630

EP - 639

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 3

ER -