BCL-2 family regulation by the 20S proteasome inhibitor bortezomib.

Bortezomib (Velcade, PS341) was licensed in 2003 as a first-in-class 20S proteasome inhibitor indicated for treatment of multiple myeloma, and is currently being evaluated clinically in a range of solid tumours. The mechanisms underlying its cancer cell toxicity are complex. A growing body of evidence suggests proteasome inhibition-dependent regulation of the BCL-2 family is a critical requirement. In particular, the stabilization of BH3-only proteins BIK, NOXA and BIM, appear to be essential for effecting BAX- and BAK-dependent cell death. These mechanisms are reviewed and the implications for favourable novel drug interactions are highlighted.Oncogene (2008) 27, 1189–1197; doi:10.1038/sj.onc.1210744; published online 10 September 2007 [ABSTRACT FROM AUTHOR]