Preclinical Activities of Bortezomib in MM, the Bone Marrow Microenvironment and Pharmacogenomics

  • Teru Hideshima
  • Paul G. Richardson
  • Kenneth C. Anderson
Part of the Milestones in Drug Therapy book series (MDT)


The intracellular protein degradation system is critical for many cellular processes, including cell cycle regulation. The proteasomes are intracellular protein complexes that degrade polyubiquitinated proteins. Bortezomib (Velcade®) is a boronic acid dipeptide that directly binds to enzymatic complex to block chimotrypsin-like activity of proteasome and is the first FDA-approved proteasome inhibitor for multiple myeloma (MM) treatment. Bortezomib blocks degradation of multi-proteins, including regulators of cell cycle, anti-apoptosis, and inflammation, as well as immune surveillance. In MM cells, bortezomib directly induces cell stress response followed by activation of c-Jun NH2 terminal kinase/stress- activated protein kinase and triggers cell cycle arrest, followed by caspase-dependent apoptosis. Bortezomib also modulates activities of non-MM cellular components, including stromal cells and osteoblasts in the bone marrow milieu. Importantly, combination treatment strategies, including histone deacetylase inhibitors, Akt inhibitor, lenalidomide, heat shock protein 90 inhibitors, and aurora kinase inhibitors demonstrate significant anti-MM activities both in preclinical and clinical studies.


Multiple Myeloma Endoplasmic Reticulum Stress Unfold Protein Response Proteasome Inhibitor Histone Deacetylase Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • Teru Hideshima
    • 1
  • Paul G. Richardson
    • 1
  • Kenneth C. Anderson
    • 1
  1. 1.Dana-Farber Cancer InstituteBostonUSA

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