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.