Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases

Li, Jianglei; Yu, Meihong; S, Fu; Liu, Deliang; Tan, Yuyong

doi:10.3389/fphar.2022.907981

Cited by 11 publications

(14 citation statements)

References 141 publications

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“…There are three HDAC6 selective inhibitors in clinical trials for cancer treatment, including ACT-1215, ACT-124, and KA2507 ( 31 ). Similar to these three HDAC6 selective inhibitors, canagliflozin showed good enzyme inhibition activity and dissociation constants to nanomolar concentrations.…”

Section: Discussionmentioning

confidence: 99%

Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis

Jiang

2022

Front. Oncol.

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Gastric cancer is a common gastrointestinal cancer. Survival outcome for patients with the recurrence or metastasis remains poor due to the lack of effective targeting drugs. The mechanisms of non-histone acetylation modifications are key epigenetic regulations that participate in various biological processes. HDAC6 is mostly located in the cytoplasm to deacetylate non-histone substrates, which has been identified as a critical promoter of many oncogenic pathways in cancers, including gastric cancer. Nevertheless, its inhibitor has not been applied in gastric cancer clinically. In this study, we identified canagliflozin as an active HDAC6-targeted inhibitor from FDA-approved Drug Library by enzymatic assay. The strong affinity of the compounds with HDAC6 was further verified by surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). In addition, molecular docking showed that canagliflozin could bind to the active pocket of HDAC6 and form interactions with key residues. Further experiments revealed that canagliflozin could effectively inhibit the migration and epithelial-mesenchymal-transition (EMT) of gastric cancer cells in vitro and in vivo. These results reveal a novel finding that canagliflozin has the potential to be an effective agent in inhibiting gastric cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis

Jiang

2022

Front. Oncol.

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“…Sequestosome1 (p62) is a multifunctional adapter protein that regulates the accumulation of protein aggregates and autophagic clearance (38). Histone deacetylase 6 (HDAC6) is a member of class IIb HDAC family and it deacetylates microtubule proteins, resulting in microtubule depolymerization and disconnection of the autophagosomal lysosomal fusion pathway (39)(40)(41), thereby inhibiting a member of the ATG8 family, LC3, which is a marker of the autophagic process. Moreover, the state of cellular redox homeostasis has a significant impact on autophagy (42).…”

Section: Iron Oxide Nanoparticles Induce Ferroptosis Via the Autophag...mentioning

confidence: 99%

Iron oxide nanoparticles induce ferroptosis via the autophagic pathway by synergistic bundling with paclitaxel

Nie,

Chen,

Zhang

et al. 2023

Mol Med Rep

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In recent years, inhibiting tumor cell activity by triggering cell ferroptosis has become a research hotspot. The development of generic targeted nanotherapeutics might bring new ideas for non-invasive applications. Currently, the potential mechanism underlying the universal application of paclitaxel (PTX)-loaded iron oxide nanoparticles (IONP@ PTX) to different types of tumors is unclear. The present study aimed to prepare IONP@PTX for targeted cancer therapy and further explore the potential mechanisms underlying the inhibitory effects of this material on the NCI-H446 human small cell lung cancer and brain M059K malignant glioblastoma cell lines. First, a CCK-8 assay was performed to determine cell viability, and then the combination index for evaluating drug combination interaction effect was evaluated. Intracellular reactive oxygen species (ROS) and lipid peroxidation levels were monitored using a DCFH-DA fluorescent probe and a C11-BODIPY™ fluorescent probe, respectively. Furthermore, western blotting assay was performed to determine the expression of autophagy-and iron death-related proteins. The experimental results showed that, compared with either IONP monotherapy, PTX monotherapy, or IONP + PTX, IONP@ PTX exerted a synergistic effect on the viability of both cell types, with significantly increased total iron ion concentration, ROS levels and lipid peroxidation levels. IONP@PTX significantly increased the expression of autophagy-related proteins Beclin 1 and histone deacetylase 6 (HDAC6) in both cell lines (P<0.05), increased the expression of light chain 3 (LC3)-II/I in NCI-H446 cells (P<0.05) and decreased that of sequestosome1 (p62) in M059K cells (P<0.05). Moreover, the addition of rapamycin enhanced the IONP@PTX-induced the upregulation of Beclin 1, LC3-II/I and HDAC6 and the downregulation of mTORC1 protein in both cell lines (P<0.05). Moreover, rapamycin enhanced the IONP@PTX-induced downregulation of p62 protein in NCI-H446 cells (P<0.05), suggesting that IONP@PTX induces ferroptosis, most likely through autophagy. Collectively, the present findings show that IONP works synergistically with PTX to induce ferroptosis via the autophagic pathway.

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“…Available evidence indicates HDAC6 is capable of modulating tumor growth, development, survival and progression via signaling pathways such as mitogen-activated protein kinases/extracellular-signal-regulated kinase (MAPK/ERK), phosphatidylinositol 3-kinase (PI3K/AKT) and p53 signaling cascade in cancers ( Figure 1 ) [ 23 , 37 , 38 , 39 , 40 , 41 , 42 ]. Of these signaling pathways, MAPK/ERK and PI3K/AKT signaling, in particular, are of importance as they are implicated in UM disease pathomechanisms [ 43 ].…”

Section: Involvement Of Hdac6 In Tumor Growth Survival and Progressionmentioning

confidence: 99%

Evaluation of the Therapeutic Potential of Histone Deacetylase 6 Inhibitors for Primary and Metastatic Uveal Melanoma

Sundaramurthi

Giricz

Kennedy

2022

IJMS

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Patients diagnosed with metastatic uveal melanoma (MUM) have a poor survival prognosis. Unfortunately for this rare disease, there is no known cure and suitable therapeutic options are limited. HDAC6 inhibitors (HDAC6i) are currently in clinical trials for other cancers and show potential beneficial effects against tumor cell survival in vitro and in vivo. In MUM cells, HDAC6i show an anti-proliferative effect in vitro and in preclinical xenograft models. The use of HDAC6 inhibitors as a treatment option for MUM should be explored further. Therefore, this review discusses (1) what is known about HDAC6i in MUM and (2) whether HDAC6 inhibitors offer a potential therapeutic option for MUM.

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Role of Selective Histone Deacetylase 6 Inhibitor ACY-1215 in Cancer and Other Human Diseases

Cited by 11 publications

References 141 publications

Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis

Canagliflozin, characterized as a HDAC6 inhibitor, inhibits gastric cancer metastasis

Iron oxide nanoparticles induce ferroptosis via the autophagic pathway by synergistic bundling with paclitaxel

Evaluation of the Therapeutic Potential of Histone Deacetylase 6 Inhibitors for Primary and Metastatic Uveal Melanoma

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