The potential of proteasome inhibitors in cancer therapy

• Published in: Expert opinion on investigational drugs Vol. 17; no. 6; p. 879
• Main Authors: Sterz, Jan, von Metzler, Ivana, Hahne, Jens-Claus, Lamottke, Britta, Rademacher, Jessica, Heider, Ulrike, Terpos, Evangelos, Sezer, Orhan
• Format: Journal Article
• Language: English
• Published: England 01.06.2008
• Subjects: Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Boronic Acids - administration & dosage; Boronic Acids - adverse effects; Boronic Acids - pharmacology; Boronic Acids - therapeutic use; Bortezomib; Cell Line, Tumor - drug effects; Clinical Trials as Topic - statistics & numerical data; Combined Modality Therapy; Drug Design; Drug Screening Assays, Antitumor; Hematologic Neoplasms - drug therapy; Hematologic Neoplasms - metabolism; Hematologic Neoplasms - surgery; Hematopoietic Stem Cell Transplantation; Humans; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - enzymology; Protease Inhibitors - administration & dosage; Protease Inhibitors - adverse effects; Protease Inhibitors - pharmacology; Protease Inhibitors - therapeutic use; Proteasome Inhibitors; Protein Processing, Post-Translational - drug effects; Protein Processing, Post-Translational - physiology; Pyrazines - administration & dosage; Pyrazines - adverse effects; Pyrazines - pharmacology; Pyrazines - therapeutic use; Salvage Therapy; Ubiquitin - physiology; Ubiquitination
• ISSN: 1744-7658
• DOI: 10.1517/13543784.17.6.879

The ubiquitin-proteasome system has become a promising novel molecular target in cancer due to its critical role in cellular protein degradation, its interaction with cell cycle and apoptosis regulation and its unique mechanism of action. This review focuses both on preclinical results and on data from clinical trials with proteasome inhibitors in cancer. Results in hematological malignancies and solid tumors were included, and important data presented in abstract form were considered in this review. Bortezomib as first-in-class proteasome inhibitor has proven to be highly effective in some hematological malignancies, overcomes conventional chemoresistance, directly induces cell cycle arrest and apoptosis, and also targets the tumor microenvironment. It has been granted approval by the FDA for relapsed multiple myeloma, and recently for relapsed mantle cell lymphoma. Combination chemotherapy regimens have been developed providing high remission rates and remission quality in frontline treatment or in the relapsed setting in multiple myeloma. The combination of proteasome inhibition with novel targeted therapies is an emerging field in oncology. Moreover, novel proteasome inhibitors, such as NPI-0052 and carfilzomib, have been developed. This review summarizes our knowledge of the ubiquitin-proteasome system and recent data from cancer clinical trials.