The ubiquitin-proteasome system as a molecular target in solid tumors: an update on bortezomib

Abstract

The ubiquitin-proteasome system has become a promising molecular target in cancer therapy due to its critical role in cellular protein degradation, interaction with cell cycle and apoptosis regulation, and unique mechanism of action. Bortezomib (PS-341) is a potent and specific reversible proteasome inhibitor, which has shown strong in vitro antitumor activity as single agent and in combination with other cytotoxic drugs in a broad spectrum of hematological and solid malignancies. In preclinical studies, bortezomib induced apoptosis of malignant cells through the inhibition of NF-|B and stabilization of pro-apoptotic proteins. Bortezomib also promotes chemo- and radiosensitization of malignant cells in vitro and inhibits tumor growth in murine xenograft models. The proteasome has been established as a relevant target in hematologic malignancies and bortezomib has been approved for the treatment of multiple myeloma. This review summarizes recent data from clinical trials in solid tumors.

Keywords: NF-κB; bortezomib; clinical studies; proteasome; solid tumors.

Figure 1

Several intra- and extracellular factors induce the intracellular increase of the IKK complex which phosphorylates the IKB protein. Phosphorylation of IKB causes its ubiquitination and degradation by 26S proteasome. NF-κB complex is then able to interact with its DNA ligand site, stimulating transcription of several genes which prompt apoptosis inhibition, growth factor increases, and cell survival. Bortezomib acts by inhibiting 26S proteasome. Abbreviation: ROS, reactive oxygen species.