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Review
. 2011 Nov;10(11):2034-42.
doi: 10.1158/1535-7163.MCT-11-0433.

Mechanism of Action of Proteasome Inhibitors and Deacetylase Inhibitors and the Biological Basis of Synergy in Multiple Myeloma

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Free PMC article
Review

Mechanism of Action of Proteasome Inhibitors and Deacetylase Inhibitors and the Biological Basis of Synergy in Multiple Myeloma

Teru Hideshima et al. Mol Cancer Ther. .
Free PMC article

Abstract

Novel agents, including the proteasome inhibitor bortezomib, have significantly improved the response and survival of patients with multiple myeloma over the last decade. Despite these advances, many patients relapse or do not benefit from the currently available therapies; thus, multiple myeloma remains an incurable disease. Deacetylase inhibitors (DACi), including panobinostat and vorinostat, have recently emerged as novel agents being evaluated in the treatment of multiple myeloma. Deacetylases are a group of enzymes with effects on various intracellular proteins, including histones, transcription factors, and molecular chaperones. Although DACi inhibit cell growth and induce apoptosis in multiple myeloma cells as a single agent, synergistic activity has been observed when they were used in combination with bortezomib. The mechanistic basis of synergy is multifactorial and includes disruption of protein degradation and inhibition of the interaction of multiple myeloma cells with the tumor microenvironment. This review summarizes recent advancements in the understanding of the mechanism of action of proteasome inhibitors and DACi in multiple myeloma and examines the biological basis of their synergistic effects. Data from the studies summarized here have been used as the rationale for the implementation of phase II and III clinical trials of DACi, alone and combined with bortezomib, in relapsed and refractory multiple myeloma.

Conflict of interest statement

Disclosure of Potential Conflict of Interest disclosure

T.H. is a consultant for Acetylon Pharmaceuticals. P.G.R. is a consultant and on advisory boards for Millennium and Celgene. K.C.A. is a consultant and on advisory board for Millennium, Celgene, and Novartis.

Figures

Figure 1
Figure 1
Molecular structures of deacetylase inhibitors and the proteasome inhibitor bortezomib.
Figure 2
Figure 2
Inhibitions of the proteasome and aggresome pathways by bortezomib and deacetylase inhibitors (DACi). Unfolded/misfolded proteins are targeted by ubiquitin for degradation by the proteasome and aggresome pathways. The proteasome inhibitor bortezomib leads to the accumulation of ubiquitin protein aggregates. These aggregates are shuttled to the lysosome, where they are degraded via the aggresome pathway. Aggresome formation involves the shuttling of the protein aggregates along microtubules by dynein motor proteins. The interaction of the unfolded/misfolded protein complexes is facilitated by histone deacetylase 6 (HDAC6). Conversely, DACi with inhibitory activity toward HDAC6 block this process. The combination of proteasome inhibitors and DACi lead to increased cellular stress and apoptosis.
Figure 3
Figure 3
Bortezomib and deacetylase inhibitors (DACi) inhibit key pathways associated with multiple myeloma (MM) cell growth and survival. Growth and survival of MM cells are dependent on functioning intracellular pathways that drive proliferation of and the interaction with the extracellular matrix (ECM) and bone marrow stromal cells (BMSC). The combination of bortezomib and DACi leads to inactivation of NF-κB and MM cell apoptosis. Both DACi and bortezomib suppress the production of cytokines including interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF1). Bortezomib also suppresses tumor necrosis factor α (TNF-α), leading to inhibition of the interaction of MM cells and BMSCs. Bortezomib has been shown to decrease the secretion of VEGF, leading to inhibition of angiogenesis. The cell surface proteoglycan syndecan 1 is downregulated by DACi, which affects the interaction of MM cells with the ECM. ICAM, intracellular adhesion molecule; LFA4, leukocyte function-associated antigen 4; STAT3, signal transducers and activators of transcription 3; VCAM, vascular cell adhesion molecule; VLA4, very late antigen 4.

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