HDAC6-selective inhibitor synergistically enhances the anticancer activity of immunomodulatory drugs in multiple myeloma

Hye Rim Won, Dong Hoon Lee, Soo Keun Yeon, Hyun Wook Ryu, Go Woon Kim, So Hee Kwon

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1 Citation (Scopus)

Abstract

Nonselective histone deacetylase (HDAC) inhibitors have therapeutic effects, but exhibit dose-limiting toxicities in patients with multiple myeloma (MM). The present study investigated the interaction between the HDAC6 inhibitor, A452, and immunomodulatory drugs (IMiDs) on dexamethasone (Dex)-sensitive and -resistant MM cells compared with the current clinically tested HDAC6 inhibitor, ACY-1215. It was shown that the combination of the HDAC6-selective inhibitor, A452, with either of the IMiDs tested (lenalidomide or pomalidomide) led to the synergistic inhibition of cell growth, a decrease in the viability of MM cells and in an increase in the levels of apoptosis. Furthermore, enhanced cell death was associated with the inactivation of AKT and extracellular signal-regulated kinase (ERK)1/2. Of note, A452 in combination with IMiDs induced synergistic MM cytotoxicity without altering the expression of cereblon and thereby, the synergistic downregulation of IKAROS family zinc finger (IKZF)1/3, c-Myc and interferon regulatory factor 4 (IRF4). Furthermore, combined treatment with A452 and IMiDs induced the synergistic upregulation of PD-L1. More importantly, this combination treatment was effective in the Dex-resistant MM cells. Overall, the findings of this study indicate that A452 is more effective as an anticancer agent than ACY-1215. Taken together, these findings suggest that a combination of the HDAC6-selective inhibitor, A452, and IMiDs may prove to be beneficial in the treatment of patients with MM.

Original languageEnglish
Pages (from-to)499-512
Number of pages14
JournalInternational journal of oncology
Volume55
Issue number2
DOIs
Publication statusPublished - 2019

Bibliographical note

Funding Information:
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2016R1D1A1A02937071 and 2018R1A6A1A03023718).

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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