Targeting the proteasome in cancer therapy

A variety of cellular constituents and metabolic processes have been exploited in the past as targets for cancer therapy. In that malignancies generally arise because of mutations of the genetic material, it is interesting to note that many of these therapies have themselves targeted DNA. Alkylating agents, one of the oldest classes of anti-tumor drugs, work in part by damaging DNA and preventing replication. Other drugs, such as taxanes and vinca alkaloids, interfere with microtubule function that is necessary to partition chromosomes after they have been faithfully copied. Still others, such as anthracyclines and camptothecins, interfere with topoisomerases, which are important in processes such as nucleic acid transcription and repair. Studies of metabolic pathways have provided many useful targets and therapeutic agents, such as folic acid metabolism, which is inhibited by methotrexate, and pyrimidine metabolism, which is inhibited by several drugs, including cytarabine. Agents that inhibit the unopposed action of certain hormones, such as the mixed anti-estrogen tamoxifen, have made important contributions to our chemotherapeutic armamentarium as well. More recent studies have focused in part on signal transduction pathways, with prominent successes such as the BCR-ABL tyrosine kinase inhibitor imatinib mesylate, which has revolutionized the care of patients with chronic myelogenous leukemia. Significant therapeutic benefits have also been achieved in targeting cell surface markers with monoclonal antibodies, most notably using rituximab, which recognizes CD20, a marker expressed commonly on Blymphocyte-derived malignancies. One area of metabolism that has previously been relatively less explored as a possible target is that of intracellular protein turnover, which occurs predominantly through the ubiquitin-proteasome pathway. However, the proteasome has now been validated as a rational target for clinical cancer therapy in multiple myeloma, and is being studied further in a variety of other tumor types as well. This chapter will review the normal role of the ubiquitin-proteasome pathway in cellular homeostasis, and some of the molecular mechanisms by which proteasome inhibitors can exert anti-tumor efficacy. The current clinical use of one inhibitor, bortezomib, will be outlined, as will future promising directions for its development.