, Volume 4, Issue 6, pp 359-372

The Proteasome as a Target for Cancer Treatment

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Abstract

Targeted degradation of key regulatory proteins is an essential element of cell-cycle control. The proteasome plays a pivotal role in the degradation of such proteins and has, therefore, become an important therapeutic target for diseases involving cell proliferation, notably malignant diseases. Several studies have demonstrated that proteasome inhibition induces apoptosis and sensitizes cancer cells to traditional tumoricidal agents (chemotherapy or irradiation), both in vitroand in vivo, by having a significant impact on the turnover of certain key cell cycle regulatory elements (p53, p21, p27, Bax, etc.) as well as central transcription factors (nuclear factor [NF]-κB). Inhibition of the latter can result in reversal of chemoresistance.

Bortezomib, a potent and selective proteasome inhibitor, is particularly promising from a therapeutic perspective; it is the only such inhibitor that has progressed to clinical trials. Results from phase I/II studies indicate that the drug is well tolerated, and bortezomib has become an effective treatment for patients with hematologic malignancies (in particular multiple myeloma). This drug also seems to have significant activity in solid tumor malignancies. Phase I/II combination studies of bortezomib and other chemotherapeutics in hematologic and solid tumors are underway.