Page 133 - Haematologica August 2018

Plasma Cell DIsorders
Therapeutic effects of the novel subtype-selective histone deacetylase inhibitor chidamide on myeloma-associated bone disease
Jingsong He,1* Qingxiao Chen,1* Huiyao Gu,1 Jing Chen,1 Enfan Zhang,1 Xing Guo,1 Xi Huang,1 Haimeng Yan,1 DongHua He,1 Yang Yang,1 Yi Zhao,1 Gang Wang,1,2 Huang He,1 Qing Yi3 and Zhen Cai1
1Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; 2Quzhou People’s Hospital, Zhejiang Province, China and 3Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, OH, USA
ABSTRACT
Histone deacetylases are promising therapeutic targets in hemato- logical malignancies. In the work herein, we investigated the effect of chidamide, a new subtype-selective histone deacetylase inhibitor that was independently produced in China, on multiple myelo- ma and its associated bone diseases using different models. The cytotox- icity of chidamide toward myeloma is due to its induction of cell apop- tosis and cell cycle arrest by increasing the levels of caspase family pro- teins p21 and p27, among others. Furthermore, chidamide exhibited sig- nificant cytotoxicity against myeloma cells co-cultured with bone mes- enchymal stromal cells and chidamide-pretreated osteoclasts. Importantly, chidamide suppressed osteoclast differentiation and resorp- tion in vitro by dephosphorylating p-ERK, p-p38, p-AKT and p-JNK and inhibiting the expression of Cathepsin K, NFATc1 and c-fos. Finally, chi- damide not only prevented tumor-associated bone loss in a disseminated murine model by partially decreasing the tumor burden but also prevent- ed rapid receptor activator of nuclear factor κ-b ligand (RANKL)-induced bone loss in a non-tumor-bearing mouse model. Based on our results, chidamide exerted dual anti-myeloma and bone-protective effects in vitro and in vivo. These findings strongly support the potential clinical use of this drug as a treatment for multiple myeloma in the near future.
Introduction
Multiple myeloma (MM) is an incurable plasma malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow (BM), the secre- tion of high levels of monoclonal immunoglobulins and osteolytic bone lesions.1 Myeloma cells interact with different cell types in the BM microenvironment, such as osteoclasts (OCs) and mesenchymal stromal cells, which supports their growth, drug resistance and the development of bone disease through cell–cell adhesion and the release of growth factors, such as interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF).1 Osteolytic bone lesions, which result from increased bone resorption by OCs and reduced osteoblastic bone formation, are the most common complication of MM and often decrease the quality of life and survival time of patients with MM.2,3 New active drugs, including proteasome inhibitors and immunomodulatory agents, have improved the outcomes of patients with MM and alleviated bone damage.1 However, disease progression is still inevitable. Therefore, the identification of new targets and development of new drugs that focus on MM cells and their BM microenvironment are crucial to the development of more effective treatments.
Chidamide is a novel oral histone deacetylase inhibitor (HDACi) designed to inhibit the activity of HDAC1, 2, 3 and 10 which is produced independently in China and is now undergoing phase I clinical trials in America and Japan.4,5
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Haematologica 2018 Volume 103(8):1369-1379
*JH and QC contributed equally to the study.
Correspondence:
caiz@zju.edu.cn
Received: November 8, 2017. Accepted: April 27, 2018. Pre-published: May 17, 2018.
doi:10.3324/haematol.2017.181172
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/8/1369
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