MPT0G413, A novel HDAC6-selective inhibitor, and bortezomib synergistically exert anti-tumor activity in multiple myeloma cells

Fang I. Huang, Yi Wen Wu, Ting Yi Sung, Jing Ping Liou, Mei Hsiang Lin, Shiow Lin Pan, Chia Ron Yang

研究成果: 雜誌貢獻文章

摘要

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.

原文英語
文章編號249
期刊Frontiers in Oncology
9
發行號APR
DOIs
出版狀態已發佈 - 一月 1 2019

指紋

Histone Deacetylases
Multiple Myeloma
Neoplasms
Histone Deacetylase Inhibitors
Growth
Ubiquitinated Proteins
Apoptosis
Dyneins
Proteins
SCID Mice
Caspase 9
Caspase 8
Caspases
Coculture Techniques
Bortezomib
Mesenchymal Stromal Cells
Ribosomes
Heterografts
Caspase 3
Bone Marrow Cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

引用此文

MPT0G413, A novel HDAC6-selective inhibitor, and bortezomib synergistically exert anti-tumor activity in multiple myeloma cells. / Huang, Fang I.; Wu, Yi Wen; Sung, Ting Yi; Liou, Jing Ping; Lin, Mei Hsiang; Pan, Shiow Lin; Yang, Chia Ron.

於: Frontiers in Oncology, 卷 9, 編號 APR, 249, 01.01.2019.

研究成果: 雜誌貢獻文章

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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.",
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AU - Liou, Jing Ping

AU - Lin, Mei Hsiang

AU - Pan, Shiow Lin

AU - Yang, Chia Ron

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KW - Bone marrow stromal cells

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