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.

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.

The HDAC6 inhibitor ACY­1215 enhances the anticancer activity of oxaliplatin in colorectal cancer cells.

ACY­1215, also known as ricolinostat, is a leading histone deacetylase 6 inhibitor, which is currently being tested in clinical trials for hematological malignancies. Previous studies have reported that ACY­1215 is not potent enough as a monotherapy for the treatment of colorectal cancer (CRC), which generally requires combination therapy for successful treatment. Therefore, the present study aimed to determine whether the synergistic interaction detected between ACY­1215 and anticancer agents in hematological cancers could occur in solid tumors. The results of the present study indicated that ACY­1215 exerted a potent synergistic anti-proliferative effect when used in combination with anticancer agents in CRC cells. The combination of ACY­1215 and oxaliplatin was more potent than either drug alone, as indicated by an increase in apoptotic cells and their effects on the apoptotic pathway; ACY­1215 and oxaliplatin cotreatment activated caspase­3 and poly (ADP ribose) polymerase, increased B­cell lymphoma (Bcl)­2 homologous antagonist/killer expression, and decreased Bcl­extra large protein, phosphorylated-extracellular signal-regulated kinase and phosphorylated-protein kinase B expression. In addition, combined treatment of ACY­1215 and anticancer agents induced synergistic upregulation of programmed death­ligand 1. These findings suggested that a therapeutic strategy that combines ACY­1215 and oxaliplatin warrants attention for the treatment of solid tumors, including CRC.

A potent hydroxamic acid-based, small-molecule inhibitor A452 preferentially inhibits HDAC6 activity and induces cytotoxicity toward cancer cells irrespective of p53 status.

HDAC6-selective inhibitors are novel epigenetic anticancer agents. However, their precise mechanisms of action are incompletely understood. We investigated the anticancer mechanisms of the novel potent and selective HDAC6 inhibitor A452 compared with current clinically tested HDAC6 inhibitor ACY-1215. We demonstrate that A452 effectively inhibits the cell growth and viability of various cancer cell types, irrespective of p53 status. A452-induced apoptosis as evidenced by activated caspase 3 and PARP, increased Bak and Bax and decreased Bcl-xL. Moreover, A452 shifted cells away from antiapoptotic (AKT and ERK) pathways and toward proapoptotic (p38) pathways. A452 triggered DNA damage via increased γH2AX and activation of the checkpoint kinase Chk2. A452 induced the suppression of cell migration and invasion. Interestingly, A452 upregulated the expression of PD-L1, which regulates the PD-1 inhibitory pathway in T cells. Overall, our results suggest that A452 is more effective as an anticancer agent than ACY-1215. Therefore, therapeutically targeting HDAC6 may represent a novel strategy for cancer treatment irrespective of the p53 mutation status.

Advances in epigenetic glioblastoma therapy.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults despite contemporary gold-standard first-line treatment strategies. This type of tumor recurs in virtually all patients and no commonly accepted standard treatment exists for the recurrent disease. Therefore, advances in all scientific and clinical aspects of GBM are urgently needed. Epigenetic mechanisms are one of the major factors contributing to the pathogenesis of cancers, including glioblastoma. Epigenetic modulators that regulate gene expression by altering the epigenome and non-histone proteins are being exploited as therapeutic drug targets. Over the last decade, numerous preclinical and clinical studies on histone deacetylase (HDAC) inhibitors have shown promising results in various cancers. This article provides an overview of the anticancer mechanisms of HDAC inhibitors and the role of HDAC isoforms in GBM. We also summarize current knowledge on HDAC inhibitors on the basis of preclinical studies and emerging clinical data.

HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery.

Histone deacetylase 6 (HDAC6) plays an important role in stress responses such as misfolded protein-induced aggresomes, autophagy, and stress granules. However, precisely how HDAC6 manages response during and after cellular stress remains largely unknown. This study aimed to investigate the effect of HDAC6 on various stress and post-stress recovery responses. We showed that HIF-1α protein levels were reduced in HDAC6 knockout (KO) MEFs compared to wild-type (WT) MEFs in hypoxia. Furthermore, under hypoxia, HIF-1α levels were also reduced following rescue with either a catalytically inactive or a ubiqiutin-binding mutant HDAC6. HDAC6 deacetylated and upregulated the stability of HIF-1α, leading to activation of HIF-1α function under hypoxia. Notably, both the deacetylase and ubiquitin-binding activities of HDAC6 contributed to HIF-1α stabilization, but only deacetylase activity was required for HIF-1α transcriptional activity. Suppression of HDAC6 enhanced the interaction between HIF-1α and HSP70 under hypoxic conditions. In addition to hypoxia, depletion of HDAC6 caused hypersensitivity to cell death during oxidative stress and post-stress recovery. However, HDAC6 depletion had no effect on cell death in response to heat shock or ionizing radiation. Overall, our data suggest that HDAC6 may serve as a critical stress regulator in response to different cellular stresses.

Influence of toxicologically relevant metals on human epigenetic regulation.

Environmental toxicants such as toxic metals can alter epigenetic regulatory features such as DNA methylation, histone modification, and non-coding RNA expression. Heavy metals influence gene expression by epigenetic mechanisms and by directly binding to various metal response elements in the target gene promoters. Given the role of epigenetic alterations in regulating genes, there is potential for the integration of toxic metal-induced epigenetic alterations as informative factors in the risk assessment process. Here, we focus on recent advances in understanding epigenetic changes, gene expression, and biological effects induced by toxic metals.