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Pharmaceuticals 2017, 10(2), 40; doi:10.3390/ph10020040

Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics

Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226, USA
Academic Editor: Jean Jacques Vanden Eynde
Received: 15 February 2017 / Revised: 28 March 2017 / Accepted: 4 April 2017 / Published: 11 April 2017
(This article belongs to the Special Issue New Drugs in Hematology)
View Full-Text   |   Download PDF [2344 KB, uploaded 11 April 2017]   |  

Abstract

The unfolded protein response is responsible for the detection of misfolded proteins and the coordination of their disposal and is necessary to maintain the cellular homoeostasis. Multiple myeloma cells secrete large amounts of immunoglobulins, proteins that need to be correctly folded by the chaperone system. If this process fails, the misfolded proteins have to be eliminated by the two main garbage-disposal systems of the cell: proteasome and aggresome. The blockade of either of these systems will result in accumulation of immunoglobulins and other toxic proteins in the cytoplasm and cell death. The simultaneous inhibition of the proteasome, by proteasome inhibitors (PIs) and the aggresome, by histone deacetylase inhibitors (HDACi) results in a synergistic increase in cytotoxicity in myeloma cell lines. This review provides an overview of mechanisms of action of second-generation PIs and HDACi in multiple myeloma (MM), the clinical results currently observed with these agents and assesses the potential therapeutic impact of the different agents in the two classes. The second-generation PIs offer benefits in terms of increased efficacy, reduced neurotoxicity as off-target effect and may overcome resistance to bortezomib because of their different chemical structure, mechanism of action and biological properties. HDACi with anti-myeloma activity in clinical development discussed in this review include vorinostat, panobinostat and selective HDAC6 inhibitor, ricolinostat. View Full-Text
Keywords: multiple myeloma; proteasome inhibitors; histone deacetylase inhibitors; clinical trials in myeloma multiple myeloma; proteasome inhibitors; histone deacetylase inhibitors; clinical trials in myeloma
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Chhabra, S. Novel Proteasome Inhibitors and Histone Deacetylase Inhibitors: Progress in Myeloma Therapeutics. Pharmaceuticals 2017, 10, 40.

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