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Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment.

ABSTRACT: Histone deacetylase (HDAC) is one of the most characterized epigenetic modifiers, modulating chromatin structure and gene expression, which plays an important role in cell cycle, differentiation and apoptosis. Dysregulation of HDAC promotes cancer progression, thus inhibitors targeting HDACs have evidently shown therapeutic efficacy in multiple cancers. Tucidinostat (formerly known as chidamide), a novel subtype-selective HDAC inhibitor, inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb HDAC10. Tucidinostat is approved in relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL), advanced breast cancer and R/R adult T-cell leukemia-lymphoma (ATLL). Compared with other HDAC inhibitors, tucidinostat shows notable antitumor activity, remarkable synergistic effect with immunotherapy, and manageable toxicity. Here, we comprehensively summarize recent advances in tucidinostat as both monotherapy and a regimen of combination therapy in both hematological and solid malignancies in clinic. Further studies will endeavor to identify more combination strategies with tucidinostat and to identify specific clinical biomarkers to predict the therapeutic effect.

SUBMITTER: Sun Y

PROVIDER: S-EPMC9481063 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment.

Sun Yichen Y Hong Jing Han JH Ning Zhiqiang Z Pan Desi D Fu Xin X Lu Xianping X Tan Jing J

Frontiers in pharmacology 20220902

Histone deacetylase (HDAC) is one of the most characterized epigenetic modifiers, modulating chromatin structure and gene expression, which plays an important role in cell cycle, differentiation and apoptosis. Dysregulation of HDAC promotes cancer progression, thus inhibitors targeting HDACs have evidently shown therapeutic efficacy in multiple cancers. Tucidinostat (formerly known as chidamide), a novel subtype-selective HDAC inhibitor, inhibits Class I HDAC1, HDAC2, HDAC3, as well as Class IIb ...[more]

PMID: 36120308

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Project description:Broxbam, also known as N-hydroxy-4-{1-methoxy-4-[4'-(3'-bromo-4',5'-dimethoxyphenyl)-oxazol-5'-yl]-2-phenoxy} butanamide, is a novel chimeric inhibitor that contains two distinct pharmacophores in its molecular structure. It has been previously demonstrated to inhibit the activity of histone deacetylases (HDAC) and tubulin polymerisation, two critical components required for cancer growth and survival. In the present study, the potential suitability of broxbam for the treatment of liver cancer was investigated. The effects of broxbam on cell proliferation and apoptosis, in addition to the underlying molecular mechanism of action, were first investigated in primary liver cancer cell lines Huh7, HepG2, TFK1 and EGI1. Real-time proliferation measurements made using the iCELLigence system and viable cell number counting following crystal violet staining) revealed that broxbam time- and dose-dependently reduced the proliferation of liver cancer cell lines with IC50 values <1 µM. In addition, a significant inhibition of the growth of hepatoblastoma microtumours on the chorioallantoic membranes (CAM) of fertilised chicken eggs by broxbam was observed according to results from the CAM assay, suggesting antineoplastic potency in vivo. Broxbam also exerted apoptotic effects through p53- and mitochondria-driven caspase-3 activation in Huh7 and HepG2 cells according to data from western blotting (p53 and phosphorylated p53), mitochondrial membrane potential measurements (JC-1 assay) and fluorometric capsase-3 measurements. Notably, no contribution of unspecific cytotoxic effects mediated by broxbam were observed from LDH-release measurements. HDAC1, -2, -4 and -6 expression was measured by western blotting and the HDAC inhibitory potency of broxbam was next evaluated using subtype-specific HDAC enzymatic assays, which revealed a largely pan-HDAC inhibitory activity with the most potent inhibition observed on HDAC6. Silencing HDAC6 expression in Huh7 cells led to a drop in the expression of the proliferation markers Ki-67 and E2F3, suggesting that HDAC6 inhibition by broxbam may serve a predominant role in their antiproliferative effects on liver cancer cells. Immunofluorescence staining of cytoskeletal proteins (α-tubulin & actin) of broxbam-treated HepG2 cells revealed a pronounced inhibition of tubulin polymerisation, which was accompanied by reduced cell migration as determined by wound healing scratch assays. Finally, data from zebrafish angiogenesis assays revealed marked antiangiogenic effects of broxbam in vivo, as shown by the suppression of subintestinal vein growth in zebrafish embryos. To conclude, the pleiotropic anticancer activities of this novel chimeric HDAC- and tubulin inhibitor broxbam suggest that this compound is a promising candidate for liver cancer treatment, which warrants further pre-clinical and clinical evaluation.

Project description:BackgroundMalignant ascites is a manifestation of end stage events in a variety of cancers and is associated with significant morbidity. Epigenetic modulators play a key role in cancer initiation and progression, among which histone deacetylases (HDACs) are considered as one of the most important regulators for various cancer development, such as liver cancer, ovarian cancer, and pancreatic cancer et al. Thus, in this paper, we sought to explore the therapeutic effect of HDAC inhibitor on malignant ascites.MethodsIn this report, we tested the therapeutic effect of different isoform selective HDAC inhibitors (Class I HDACI MS275, Class IIa HDACI MC1568, pan-HDAC inhibitors SAHA) on malignant ascites in vitro and in vivo. We further used proteome analysis to find the potential mechanisms for malignant ascites therapy.ResultsAmong the different isoform-selective HDAC inhibitors, the class I selective HDACI, MS275, exhibited preferential inhibition on various ascites cells. MS275 could induce cell cycle arrest in G0/G1 phase and promote apoptosis on ascites cells. Through proteome analysis, we found MS275 could downregulate proteins related to cell cycle progression, such as CDK4, CDC20, CCND1; MS275 could upregulate pro-apoptosis proteins such as PAPR1, LMNB2 and AIFM1; in addition, MS275 could change the expression of tumorigenic proteins related to the specific malignant ascites bearing tumors, such as TSP1 and CDK4 for bladder cancer. We then confirmed that abemaciclib (CDK4/6 selective inhibitor) could inhibit the proliferation of ascites cells, and the combination of abemaciclib and MS275 had synergistic anti-tumor effect. Finally, we found that MS275 could in vivo inhibit malignant ascites progression (ascites volume: 2.9 ± 1.0 mL vs 7.5 ± 1.2 mL, p < 0.01), tumor growth, and prolong 66% of the life-span when compared with the untreated group.ConclusionThis present research revealed that the class I selective HDAC inhibitor, MS275, could effectively inhibit malignant ascites development and tumor growth via multiple pathways. These results indicated that HDACI could have great potential for clinical therapy of malignant ascites.

Project description:BackgroundAlthough targeting histone deacetylases (HDACs) may be an effective strategy for core binding factor-acute myeloid leukemia (CBF-AML) harboring t(8;21) or inv(16), HDAC inhibitors are reported to be limited by drug-resistant characteristic. Our purpose is to evaluate the anti-leukemia effects of Baicalein on CBF-AML and clarify its underlying mechanism.MethodsEnzyme activity assay was used to measure the activity inhibition of HDACs. Rhodamine123 and RT-qPCR were employed to evaluate the distribution of drugs and the change of ATP-binding cassette (ABC) transporter genes. CCK8, Annexin V/PI, and FACS staining certified the effects of Baicalein on cell growth, apoptosis, and differentiation. Duolink and IP assay assessed the interaction between HDAC-1 and ubiquitin, HSP90 and AML1-ETO, and Ac-p53 and CBFβ-MYH11. AML cell lines and primary AML cells-bearing NOD/SCID mice models were used to evaluate the anti-leukemic efficiency and potential mechanism of Baicalein in vivo.ResultsBaicalein showed HDAC-1/8 inhibition to trigger growth suppression and differentiation induction of AML cell lines and primary AML cells. Although the inhibitory action on HDAC-1 was mild, Baicalein could induce the degradation of HDAC-1 via ubiquitin proteasome pathway, thereby upregulating the acetylation of Histone H3 without promoting ABC transporter genes expression. Meanwhile, Baicalein increased the acetylation of HSP90 and lessened its connection to AML1/ETO, consequently leading to degradation of AML1-ETO in t(8;21)q(22;22) AML cells. In inv(16) AML cells, Baicalein possessed the capacity of apoptosis induction accompanied with p53-mediated apoptosis genes expression. Moreover, CBFβ-MYH11-bound p53 acetylation was restored via HDAC-8 inhibition induced by Baicalein contributing the diminishing of survival of CD34+ inv(16) AML cells.ConclusionsThese findings improved the understanding of the epigenetic regulation of Baicalein, and warrant therapeutic potential of Baicalein for CBF-AML.

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Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment.

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Therapeutic potential of tucidinostat, a subtype-selective HDAC inhibitor, in cancer treatment.

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