The selective HDAC6 inhibitor Nexturastat A induces apoptosis, overcomes drug resistance and inhibits tumor growth in multiple myeloma

• Published in: Bioscience reports Vol. 39; no. 3
• Main Authors: Sun, Xiaoyang, Xie, Yu, Sun, Xiaoshen, Yao, Yao, Li, Hujun, Li, Zhenyu, Yao, Ruosi, Xu, Kailin
• Format: Journal Article
• Language: English
• Published: England Portland Press Ltd 29.03.2019
• Subjects: Animals; Apoptosis - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Drug Resistance, Neoplasm - drug effects; G1 Phase Cell Cycle Checkpoints - drug effects; Histone Deacetylase 6 - antagonists & inhibitors; Histone Deacetylase 6 - metabolism; Histone Deacetylase Inhibitors - pharmacology; Humans; Hydroxamic Acids - pharmacology; Mice, SCID; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Phenylurea Compounds - pharmacology; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; apoptosis; Nexturastat A; multiple myeloma; drug resistance; p21
• ISSN: 0144-8463; 1573-4935
• DOI: 10.1042/BSR20181916

Multiple myeloma (MM) is a hematological malignancy of plasma cells that produce a monoclonal immunoglobulin protein. Despite significant advances in the treatment of MM, challenges such as resistance to therapy remain. Currently, inhibition of histone deacetylases (HDACs) is emerging as a potential method for treating cancers. Numerous HDAC inhibitors are being studied for the use in monotherapy or in conjunction with other agents for MM. In the present study, we investigated the anti-myeloma effect of Nexturastat A (NexA), a novel selective HDAC6 inhibitor. We found that NexA impaired MM cells viability in a dose- and time-dependent manner. NexA also provoked a cell cycle arrest at the G1 phase in MM cells Furthermore, NexA promoted apoptosis of MM cells via transcriptional activation of the p21 promoter, which may through its ability to up-regulate the H3Ac and H4Ac levels. Additionally, NexA could overcome bortezomib (BTZ) resistance in MM cells, and NexA in combination with BTZ had stronger efficacy. We also confirmed that NexA inhibited tumor growth in murine xenograft models of MM. These interesting findings provided the rationale for the future advancement of this novel HDAC6 inhibitor as a potential therapeutic anti-myeloma agent.