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Bortezomib in the Treatment of Multiple Myeloma pp 29–42Cite as

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

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Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

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.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, Boston, MA, 02115, USA

    Teru Hideshima, Paul G. Richardson & Kenneth C. Anderson

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  1. Teru Hideshima
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  2. Paul G. Richardson
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  3. Kenneth C. Anderson
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Correspondence to Teru Hideshima .

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Editors and Affiliations

  1. Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    Irene M. Ghobrial

  2. Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    Paul G. Richardson

  3. Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    Kenneth C. Anderson

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Hideshima, T., Richardson, P.G., Anderson, K.C. (2011). Preclinical Activities of Bortezomib in MM, the Bone Marrow Microenvironment and Pharmacogenomics. In: Ghobrial, I., Richardson, P., Anderson, K. (eds) Bortezomib in the Treatment of Multiple Myeloma. Milestones in Drug Therapy. Springer, Basel. https://doi.org/10.1007/978-3-7643-8948-2_2

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