Proteasome inhibitors and modulators of heat shock protein function

The proteasome is a multi-catalytic proteinase complex that is integral to intracellular proteolysis, and plays a key role in many critical functions. Inhibition of the proteasome induces cell cycle arrest and apoptosis in a variety of tumor cell types in vitro and in vivo, thus making it an attractive therapeutic agent for the treatment of cancer. Bortezomib (VELCADE®; formerly PS-341) is the first proteasome inhibitor to enter into clinical practice. Phases I–III clinical trials have shown bortezomib and proteasome inhibition to be well tolerated. Impressive anti-tumor activity against relapsed and refractory multiple myeloma has been seen, leading to the approval of bortezomib for this indication, where it seems poised to change the natural history of the disease. Additional studies are ongoing to define its role in initial therapy of myeloma, as well as in other areas, such as non-Hodgkin's lymphoma. While bortezomib has displayed less activity as a single agent against solid tumors, new research into combination regimens with other chemotherapeutics holds promise to increase efficacy against both solid tumors and hematologic malignancies. Heat shock proteins (HSPs) are molecular chaperones that interact with the ubiquitin-proteasome pathway, and function to aid in de novo protein folding and to stabilize key intracellular signaling proteins. Many tumors overexpress high-affinity HSPs that form unusually stable interactions with oncogenic client proteins, while normal, adjacent tissues only exhibit a latent, low-affinity form. Phase I/II clinical trials are ongoing with two potent HSP-90 inhibitors, which have so far been well tolerated in patients with some activity in hematologic malignancies. Drugs that modulate protein turnover through the proteasome, and protein folding through HSPs, seem destined to form an important part of our therapeutic armamentarium against a variety of malignancies.