HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma.

Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Combination treatment of A452 and BTZ or carfilzomib (CFZ) synergistically reduces BTZ-resistant markers. Additionally, A452 synergizes with BTZ or CFZ to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3), resulting in decreased expressions of low-molecular-mass polypeptide 2 (LMP2) and LMP7. Furthermore, combining A452 with BTZ or CFZ leads to synergistic cancer cell growth inhibition, viability decreases, and apoptosis induction in the BTZ-resistant MM cells. Overall, the synergistic effect of A452 with CFZ is more potent than that of A452 with BTZ in BTZ-resistant U266 cells. Thus, our findings reveal the HDAC6-selective inhibitor as a promising therapy for BTZ-chemoresistant MM.

A452, HDAC6-selective inhibitor synergistically enhances the anticancer activity of immunomodulatory drugs in IMiDs-resistant multiple myeloma.

Multiple Myeloma (MM) is a hematological malignancy of plasma cells. Although advanced therapies have elevated MM survival rate, MM eventually relapses. Relapsed/refractory MM (R/R MM) cells gain resistance to previously used drugs, which reduces treatment options. In this study, we propose a newly synthesized HDAC6-selective inhibitor, A452, as a strategy to overcome resistance to immunomodulatory drugs (IMiDs), the principal MM therapeutic drugs. Here, we identified that A452 alone reduces the viability and growth of IMiDs-resistant cells as well as synergistically reduces viability when combined with IMiDs. We confirmed that this anticancer activity occurrs by inducing apoptosis. To determine if A452 overcomes IMiDs resistance, we checked the change in the protein level of IMiDs direct/indirect targets. As a result, the combination of A452 and IMiDs slightly increased CRBN and decreased Aiolos and Ikaros, the targets of CRBN. Moreover, A452 decreased c-Myc and IRF-4 when combined with IMiDs. These data suggest that A452 helps to overcome the resistance of IMiDs. Finally, significant synergy of anticancer activity was detected when using triple combinations of A452, IMiDs, and dexamethasone. In conclusion, the novel HDAC6-selective inhibitor A452 would be beneficial to combination therapy, including IMiDs in R/R MM as a strategy for overcoming IMiDs resistance.

Temozolomide-resistant Glioblastoma Depends on HDAC6 Activity Through Regulation of DNA Mismatch Repair.

BACKGROUND/AIM: Histone deacetylase 6 (HDAC6) is considered as one of the most promising targets in drug development for cancer therapy. Drug resistance is a major cause of treatment failure in many cancers including glioblastoma (GBM), the most lethal malignant tumor. The role of HDAC6 in GBM resistance and its underlying mechanisms have not been well elucidated. Herein, we investigated the function of HDAC6 in modulating GBM resistance. MATERIALS AND METHODS: The anticancer effects of four structurally distinct selective HDAC6 inhibitors were addressed using western blot, flow cytometry, CCK-8 assay, and CI in temozolomide (TMZ)-resistant GBM cells. RESULTS: We showed that HDAC6-selecitve inhibitors block activation of the EGFR and p53 pathways in TMZ-resistant GBM cells. Importantly, the inhibition of HDAC6 correlates with increased levels of MSH2 and MSH6, key DNA mismatch repair proteins, in TMZ-resistant GBM cells. In addition to the MSH, HDAC6 inhibitors decrease MGMT expression in TMZ-resistant GBM cells. Furthermore, HDAC6 inhibitors increase TMZ sensitivity and efficiently induce apoptosis in TMZ-resistant GBM cells. CONCLUSION: Selective inhibition of HDAC6 may be a promising strategy for the treatment of TMZ-resistant GBM.

HDAC6­selective inhibitor synergistically enhances the anticancer activity of immunomodulatory drugs in multiple myeloma.

Nonselective histone deacetylase (HDAC) inhibitors have therapeutic effects, but exhibit dose­limiting 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, ACY­1215. It was shown that the combination of the HDAC6­selective 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 signal­regulated 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, c­Myc and interferon regulatory factor 4 (IRF4). Furthermore, combined treatment with A452 and IMiDs induced the synergistic upregulation of PD­L1. More importantly, this combination treatment was effective in the Dex­resistant MM cells. Overall, the findings of this study indicate that A452 is more effective as an anticancer agent than ACY­1215. Taken together, these findings suggest that a combination of the HDAC6­selective inhibitor, A452, and IMiDs may prove to be beneficial in the treatment of patients with MM.

A452, an HDAC6-selective inhibitor, synergistically enhances the anticancer activity of chemotherapeutic agents in colorectal cancer cells.

Although histone deacetylase inhibitors (HDACi) alone could be clinically useful, these are most recently used in combination with other anticancer agents in clinical trials for cancer treatment. Recently, we reported the anticancer activity of an HDAC6-selective inhibitor A452 toward various cancer cell types. This study aims to present a potent synergistic antiproliferative effect of A452/anticancer agent treatment in colorectal cancer cells (CRC) cells, independently of the p53 status. A452 in combination with irinotecan, or SAHA is more potent than either drug alone in the apoptotic pathway as evidenced by activated caspase-3 and PARP, increased Bak and pp38, decreased Bcl-xL, pERK, and pAKT, and induced apoptotic cells. Furthermore, A452 enhances DNA damage induced by anticancer agents as indicated by the increased accumulation of γH2AX and the activation of the checkpoint kinase Chk2. The silencing of HDAC6 enhances the cell growth inhibition and cell death caused by anticancer agents. In addition, A452 induces the synergistic suppression of cell migration and invasion. This study suggests a mechanism by which HDAC6-selective inhibition can enhance the efficacy of specific anticancer agents in CRC cells.