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

Int J Oncol. 2019 Aug;55(2):499-512. doi: 10.3892/ijo.2019.4828. Epub 2019 Jun 20.


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.

MeSH terms

  • Apoptosis
  • Benzene Derivatives / pharmacology
  • Cell Proliferation
  • Drug Synergism*
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Immunologic Factors / pharmacology*
  • Lenalidomide / pharmacology
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology*
  • Thalidomide / analogs & derivatives
  • Thalidomide / pharmacology
  • Tumor Cells, Cultured


  • A452 compound
  • Benzene Derivatives
  • Histone Deacetylase Inhibitors
  • Immunologic Factors
  • Thalidomide
  • pomalidomide
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Lenalidomide