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.
Fennell
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DA
Thoracic Oncology Research Group, Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, UK. d.fennell@qub.ac.uk
Chacko
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A
Mutti
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D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D005810:Multigene Family / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology*