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.

• Authors: S Vincent Rajkumar, Paul G Richardson, Teru Hideshima, Kenneth C Anderson
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 23 Issue 3 Pg. 630-9 (Jan 20 2005) ISSN: 0732-183X [Print] United States
• PMID: 15659509 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review)

Chemical References

• Boronic Acids
• Protease Inhibitors
• Proteasome Inhibitors
• Pyrazines
• Ubiquitin
• Bortezomib
• Proteasome Endopeptidase Complex
• ATP dependent 26S protease

Topics

• Apoptosis
• Boronic Acids (adverse effects, pharmacology, therapeutic use)
• Bortezomib
• Clinical Trials as Topic
• Disease Progression
• Drug Resistance, Neoplasm
• Humans
• Neoplasms (drug therapy, physiopathology)
• Protease Inhibitors (adverse effects, pharmacology, therapeutic use)
• Proteasome Endopeptidase Complex
• Proteasome Inhibitors
• Pyrazines (adverse effects, pharmacology, therapeutic use)
• Ubiquitin (pharmacology)