Proteasome Inhibition as a Novel Strategy for Cancer Treatment

Chapter
Part of the Cell Death in Biology and Diseases book series (CELLDEATH)

Abstract

The proteasome is a multi-subunit protease complex, responsible for the degradation of misfolded, damaged, or short-lived proteins. Indeed, more than 90 % of intracellular proteins are degraded through the ubiquitin–proteasome system (UPS). The UPS is extensively involved in various cellular events, including cell cycle, cell signaling, stress response, and apoptosis. Inhibition of proteasome function could result in growth arrest and/or cell death. The involved molecular mechanisms include dysregulation of the cell cycle, inactivation of NF-κB pathway, disturbance of the pro- and anti-apoptotic balance, induction of unfolded protein response, and induction of oxidative stress. The observation that suppression of proteasome function by small chemical inhibitors was able to induce apoptosis in cancer cells but not in normal cells supports the hypothesis that the proteasome could be a valuable target for cancer treatment. This idea has been validated from benchtop to bedside. In 2003, the first proteasome inhibitor anticancer drug, bortezomib, was approved in the United States for the treatment of multiple myeloma and mantle cell lymphoma. While bortezomib achieved great success in clinical applications, problems such as resistance, dose-limiting toxicities, unsatisfied efficacy in solid tumors, and interaction with some natural compounds have been observed. Therefore, it is necessary to further investigate the proteasome inhibition-mediated mechanism of cell death as well as the development of novel, new-generation proteasome inhibitors with lower toxicity and wider applications.

Keywords

Lymphoma Adduct Paclitaxel Dexamethasone Doxorubicin 

Notes

Acknowledgments

The authors thank Sara Schmitt and Daniela Buac for critical reading of the manuscript. This work was partially supported by the National Cancer Institute (1R01CA120009, 3R01CA120009-04S1, and 5R01CA127258-05, to QPD).

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Karmanos Cancer Institute and Department of PharmacologyWayne State University School of MedicineDetroitUSA

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