The Proteasome and Proteasome Inhibitors in Cancer Therapy

The proteasome, a multicatalytic proteinase complex, is responsible for the majority of intracellular protein degradation. Pharmacologic inhibitors of the proteasome possess in vitro and in vivo antitumor activity, and bortezomib, the first such agent to undergo clinical testing, has significant efficacy against multiple myeloma and non-Hodgkin lymphoma (NHL). Preclinical studies demonstrate that proteasome inhibition potentiates the activity of other cancer therapeutics, in part by down regulating chemoresistance pathways. Early clinical studies of bortezomib-based combinations, showing encouraging activity, support this observation. Molecular characterization of resistance to proteasome inhibitors has revealed novel therapeutic targets for sensitizing malignancies to these agents, such as the heat shock pathway. Below, we review the pharmacologic, preclinical, and clinical data that have paved the way for the use of proteasome inhibitors for cancer therapy; outline strategies aimed at enhancing the efficacy of proteasome inhibitors; and review other potential targets in the ubiquitin proteasome pathway for the treatment of cancer. Expected online publication date for the Annual Review of Pharmacology and Toxicology Volume 46 is January 6, 2006. Please see http://www.annualreviews.org/catalog/pub_dates.asp for revised estimates.

Voorhees PM, Orlowski RZ.

Department of Medicine, Division of Hematology/Oncology, University of North Carolina, Chapel Hill, NC 27599 Peter_Voorhees@med.unc.edu.