The proteasome: a worthwhile target for the treatment of solid tumours?

Proteasomes have a fundamental function since they degrade numerous different proteins, including those involved in the regulation of the cell cycle. Proteasome inhibition is a novel approach to the treatment of solid tumours. PS-341 (bortezomib) is a small, cell-permeable molecule that selectively inhibits the proteasome binding it in a reversible manner. The proteasome has been established as an important target in haematologic malignancies and has been approved for the treatment of multiple myeloma. Bortezomib induces apoptosis of malignant cells through the inhibition of NF-kappaB and stabilisation of proapoptotic proteins. In preclinical studies, bortezomib also promoted chemo and radiosensitisation of malignant cells in vitro and inhibited tumour growth in murine xenografts models. The single-agent and combination studies of bortezomib in solid tumours are detailed.