MPT0G413, A novel HDAC6-selective inhibitor, and bortezomib synergistically exert anti-tumor activity in multiple myeloma cells
Journal
Frontiers in Oncology
Journal Volume
9
Journal Issue
APR
Pages
249
Date Issued
2019
Author(s)
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. Copyright ? 2019 Huang, Wu, Sung, Liou, Lin, Pan and Yang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Subjects
Bone marrow stromal cells; Bortezomib; Combination therapy; Histone deacetylase 6; Multiple myeloma cells; Synergistic effect
SDGs
Other Subjects
bortezomib; caspase 3; caspase 8; caspase 9; dynein adenosine triphosphatase; histone deacetylase 6; interleukin 6; MPT0G413 inhibitor; protein inhibitor; unclassified drug; vascular cell adhesion molecule 1; vasculotropin; animal cell; animal experiment; animal model; antineoplastic activity; apoptosis; Article; bone marrow cell; bone marrow stroma cell; cancer inhibition; cell adhesion; cell adhesion assay; cell growth; cell mediated cytotoxicity; cell proliferation assay; colorimetry; down regulation; enzyme linked immunosorbent assay; human; human cell; IC50; immunoblotting; immunofluorescence test; immunoprecipitation; male; microenvironment; mouse; MTT assay; multiple myeloma; multiple myeloma cell line; nonhuman; protein expression; synergistic effect; tumor growth; ubiquitination; xenograft
Type
journal article