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

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.