Abstract
In multiple myeloma (MM), homeostasis is largely maintained by misfolded protein clearance via the proteasomal and aggresomal pathways. Histone deacetylase 6 (HDAC6) binds polyubiquitinated proteins and dynein motors and transports this protein cargo to the aggresome for further degradation. Accordingly, a combination of an HDAC6 inhibitor and bortezomib (BTZ) could increase ubiquitinated protein accumulation, leading to further apoptosis. Here we evaluated the anti-MM activity of MPT0G413, a novel specific HDAC6 inhibitor, using in vitro and in vivo models. MPT0G413 treatment more significantly inhibited cell growth in MM cells than in normal bone marrow cells. Furthermore, the combination of MPT0G413 and BTZ enhanced polyubiquitinated protein accumulation and synergistically reduced MM viability, increased caspase-3, caspase-8, caspase-9 levels, and cleaved poly (ADP) ribosome polymerase and also inhibited adherence of MM cells to bone marrow stromal cells (BMSC) and reduced VEGF and IL-6 levels and cell growth in a co-culture system. The combination treatment disturbed the bone marrow microenvironment and induced synergic, caspase-dependent apoptosis. Xenograft tumor growth significantly decreased in combination-treated SCID mice. In conclusion, MPT0G413 and BTZ synergistically inhibit MM viability, providing a framework for the clinical evaluation of combined therapies for MM.
Highlights
Multiple myeloma (MM) is a B cell malignancy characterized by the proliferation of bone marrow (BM) plasma cells and the production of large amounts of abnormal immunoglobulins [1] In the United States, it was estimated that 30,770 new MM cases would be diagnosed in 2018, accounting for 1.8% of newly diagnosed cancer cases [2]
We described the synthesis of this molecule and demonstrated its ability to inhibit Histone deacetylase 6 (HDAC6) with an IC50 value of 3.92 nM
MPT0G413 was added to the cultures of two MM cell lines, Roswell Park Memorial Institute medium (RPMI)-8226, NCI-H929, as well as to the bone marrow stromal cells (BMSC) line HS-5, and the GI50 values were evaluated
Summary
Multiple myeloma (MM) is a B cell malignancy characterized by the proliferation of bone marrow (BM) plasma cells and the production of large amounts of abnormal immunoglobulins [1] In the United States, it was estimated that 30,770 new MM cases would be diagnosed in 2018, accounting for 1.8% of newly diagnosed cancer cases [2]. MM treatment outcomes have improved since the approval of thalidomide-related immunomodulatory drugs and the proteasome inhibitor bortezomib by the FDA. Recent clinical studies have evaluated the use of pan-HDAC inhibitors, such as vorinostat (suberoylanilide hydroxamic acid, SAHA) or panobinostat (LBH589) in combination with bortezomib (BTZ) to inhibit both proteasomal and aggresomal protein degradation and overcome clinical resistance to BTZ [9]. The side effects of regimens combining pan-HDAC inhibitors and BTZ, which include fatigue, diarrhea, nausea [10], QT-interval prolongation [11, 12], and thrombocytopenia [13], limit the clinical utility of these combination treatments [14]
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