Rationale for the treatment of solid tumors with the proteasome inhibitor bortezomib.

Given its role in cellular metabolism, the proteasome could prove to be a critical target that can be exploited in treating cancer. In preclinical studies, several mechanisms for bortezomib's activity in multiple myeloma cells have been identified (e.g., NF-kappaB inhibition); antitumor activity with bortezomib has been seen in myeloma patients, thereby supporting the validity of the preclinical work. Similar mechanisms may be in play in solid tumors, and cell culture and xenograft data suggest bortezomib may be active in a wide range of tumor types. One promising possibility is the use of bortezomib for the treatment of chemoresistant tumors. Chemoresistance can be caused by a number of cellular factors; NF-kappaB is a prominent instigator of chemoresistance, and proteasome inhibition was an effective means of preventing NF-kappaB activation in myeloma and several solid tumor laboratory studies. However, the inhibition of NF-kappaB may not be the only mechanism for antitumor activity. This review explores the use of proteasome inhibitors to subvert intrinsic resistance mechanisms, disrupt inducible chemoresistance, or augment the mechanisms of action of standard chemotherapeutics. Thus, in addition to providing another target for anticancer treatment, proteasome inhibition may also provide a means to treat refractory tumors.