Abstract
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.
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Acknowledgements
DAF is supported by a Cancer Research UK Clinican Scientist Fellowship. We thank P Johnston, G Gaudino, R De Costa and K Chan for discussions.
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Fennell, D., Chacko, A. & Mutti, L. BCL-2 family regulation by the 20S proteasome inhibitor bortezomib. Oncogene 27, 1189–1197 (2008). https://doi.org/10.1038/sj.onc.1210744
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DOI: https://doi.org/10.1038/sj.onc.1210744
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