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Frontiers in Immunology 2023Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy,... (Review)
Review
Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy, chemotherapy, targeted drug therapy and immunotherapy. In recent years, immunotherapy has potentiated the survival of certain breast cancer patients; however, primary resistance or acquired resistance attenuate the therapeutic outcomes. Histone acetyltransferases induce histone acetylation on lysine residues, which can be reversed by histone deacetylases (HDACs). Dysregulation of HDACs mutation and abnormal expression contributes to tumorigenesis and tumor progression. Numerous HDAC inhibitors have been developed and exhibited the potent anti-tumor activity in a variety of cancers, including breast cancer. HDAC inhibitors ameliorated immunotherapeutic efficacy in cancer patients. In this review, we discuss the anti-tumor activity of HDAC inhibitors in breast cancer, including dacinostat, belinostat, abexinostat, mocetinotat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. Moreover, we uncover the mechanisms of HDAC inhibitors in improving immunotherapy in breast cancer. Furthermore, we highlight that HDAC inhibitors might be potent agents to potentiate immunotherapy in breast cancer.
Topics: Humans; Female; Histone Deacetylases; Histone Deacetylase Inhibitors; Breast Neoplasms; Vorinostat; Immunotherapy
PubMed: 36969235
DOI: 10.3389/fimmu.2023.1164514 -
Journal of Biomolecular Structure &... Mar 2022Epigenetic changes, histone acetylation and deacetylation in chromatin have been intensively studied due to their significance in regulating the gene expression....
Epigenetic changes, histone acetylation and deacetylation in chromatin have been intensively studied due to their significance in regulating the gene expression. According to the type of tumor, the levels of histone deacetylases (HDAC) are varied. HDAC inhibitors are a new promising class of compounds that inhibit the proliferation of tumor cells. In this study, the inhibitory efficacy of some HDAC inhibitors such as vorinostat, panobinostat, abexinostat, belinostat, resminostat, dacinostat and pracinostat was studied using molecular dynamics simulation. The inhibitory efficacy was estimated by computing the enzyme's stability, positional stability of the individual amino acids and interaction energies of HDLP-inhibitor complexes. It is hoped that this investigation may improve our understanding of the atomic-level description of the inhibitor binding site and how the HDAC inhibitors change the environment of the enzyme's active site. The results obtained from the root-mean-square deviation, the radius of gyration, solvent-accessible surface area, root-mean-square fluctuation, stride server and Ramachandran plot have revealed that the stability of HDLP enzyme with vorinostat, panobinostat and abexinostat is higher than the other studied complexes. According to the calculated values for MM-PBSA, LIE, semi-LIE binding free energies and interaction energies, the stability of the HDLP enzyme varies as panobinostat > abexinostat > vorinostat where resminostat complex showed relatively low stability. The ligandability and drugability values also give the same trend as above. The findings revealed that the panobinostat and abexinostat are potential lead compounds as reference inhibitor vorinostat. Therefore, it is possible to use these drugs as HDAC inhibitors in clinical practices. Also, the outcomes of this study could be utilized to identify new inhibitors for clinical research.Communicated by Ramaswamy H. Sarma.
Topics: Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Molecular Dynamics Simulation; Neoplasms
PubMed: 33131428
DOI: 10.1080/07391102.2020.1838328 -
BMC Chemistry Feb 2024Broad-spectrum histone deacetylase inhibitors (HDACi) have excellent anti-tumor effects, such as abexinostat, which was a novel oral HDACi that was widely used in...
Broad-spectrum histone deacetylase inhibitors (HDACi) have excellent anti-tumor effects, such as abexinostat, which was a novel oral HDACi that was widely used in clinical treatment. The purpose of this study was to establish a rapid and reliable method for the detection of abexinostat concentrations in rat plasma using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The mobile phase we used was acetonitrile and 0.1% formic acid, and the internal standard (IS) was givinostat. Selective reaction monitoring (SRM) was used for detection with ion transitions at m/z 397.93 → 200.19 for abexinostat and m/z 422.01 → 186.11 for givinostat, respectively. The intra-day and inter-day precision of abexinostat were less than 11.5% and the intra-day and inter-day accuracy ranged from - 10.7% to 9.7% using this method. During the analysis process, the stability of the test sample was reliable. In addition, the recovery and matrix effects of this method were within acceptable limits. Finally, the method presented in this paper enabled accurate and quick determination of abexinostat levels in rat plasma from the pharmacokinetic study following gavage at a dose of 8.0 mg/kg abexinostat.
PubMed: 38378603
DOI: 10.1186/s13065-024-01144-z -
The International Journal of... Aug 2020Histone deacetylase inhibitors (HDACis) affect DNA repair pathways by modulating multiple cellular machineries, including chromatin state, DNA repair factor...
Histone deacetylase inhibitors (HDACis) affect DNA repair pathways by modulating multiple cellular machineries, including chromatin state, DNA repair factor modification, and the cell cycle. These machineries can differentially affect DNA repair outcomes. With the aim to investigate the impacts of HDACis on DNA repair following CRISPR/Cas9 cleavage from the mixed actions, we used two pan-HDACis, trichostatin A (TSA) and PCI-24781, to treat animal immortalized and primary cells, and studied CRISPR/Cas9-mediated genome editing results by nonhomologous end joining (NHEJ) and homology-directed repair (HDR) pathways. We first found that TSA and PCI-24781 increased NHEJ efficiency. However, further analysis of the total NHEJ events demonstrated that alternative end joining (alt-EJ) mainly contributed to the enhanced total NHEJ by HDACis. We then analyzed HDR efficiency with HDACi treatment and found that multiple HDR pathways, including homologous recombination, single strand annealing and single-stranded oligonucleotide (ssODN)-mediated HDR, were all increased with HDACi treatment. TSA also increased CRISPR-induced ssODN-mediated HDR rate in pig parthenogenetic embryos. Analyzing acetylation status of DNA repair factors showed that acetylation levels of classical NHEJ (c-NHEJ) factors KU70 and KU80 and alt-EJ factor PARP1 were significantly enhanced, but alt-EJ factor LIG3 and HDR factors Rad51 and Rad52 were not affected greatly, implying a differential impact on these repair pathways by HDACis. In addition, TSA and PCI-24781 can enrich cells in G2/M phase of the cell cycle which is beneficial for occurrence of HDR. These findings show that HDACis can effectively promote CRISPR-mediated homology-involved DNA repair, including HDR and alt-EJ pathways, through concerted action of multiple cellular machineries.
Topics: Acetylation; Animals; Benzofurans; CRISPR-Cas Systems; Cell Cycle; Cells, Cultured; Chromatin Immunoprecipitation; DNA End-Joining Repair; DNA Repair; Gene Editing; HEK293 Cells; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Ku Autoantigen; Poly (ADP-Ribose) Polymerase-1; Rad51 Recombinase; Rad52 DNA Repair and Recombination Protein; Recombinational DNA Repair; Swine
PubMed: 32534122
DOI: 10.1016/j.biocel.2020.105790 -
Theranostics 2021Histone deacetylases (HDACs) are involved in key cellular processes and have been implicated in cancer. As such, compounds that target HDACs or drugs that target...
Histone deacetylases (HDACs) are involved in key cellular processes and have been implicated in cancer. As such, compounds that target HDACs or drugs that target epigenetic markers may be potential candidates for cancer therapy. This study was therefore aimed to identify a potential epidrug with low toxicity and high efficiency as anti-tumor agents. : We first screened an epigenetic small molecule inhibitor library to screen for an epidrug for breast cancer. The candidate was identified as PCI-24781 and was characterized for half maximal inhibitory concentration (IC), for specificity to breast cancer cells, and for effects on carcinogenesis and metastatic properties of breast cancer cell lines . A series of in silico and analyses were further performed of PCI-24781 to identify and understand its target. : Screening of an epigenetic inhibitor library in MDA-MB-231 cells, a malignant cancer cell line, showed that PCI-24781 is a potential anti-tumor drug specific to breast cancer. Ca related pathways were identified as a potential target of PCI-24781. Further analyses showed that PCI-24781 inhibited Gαq-PLCβ3-mediated calcium signaling by activating the expression of regulator of G-protein signaling 2 (RGS2) to reduce cell proliferation, metastasis, and differentiation, resulting in cell death in breast cancer. In addition, RGS2 depletion reversed anti-tumor effect and inhibition of calcium influx induced by PCI-24781 treatment in breast cancer cells. : We have demonstrated that PCI-24781 is an effective anti-tumor therapeutic agent that targets calcium signaling by activating RGS2. This study also provides a novel perspective into the use of HDAC inhibitors for cancer therapy.
Topics: Animals; Apoptosis; Benzofurans; Breast Neoplasms; Calcium; Cell Proliferation; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Mice; Mice, Inbred BALB C; Mice, Nude; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 33500709
DOI: 10.7150/thno.48314 -
Gene Nov 2022Identifying suitable deregulated targets in autophagy pathway is essential for developing autophagy modulating cancer therapies. With this aim, we systematically...
Identifying suitable deregulated targets in autophagy pathway is essential for developing autophagy modulating cancer therapies. With this aim, we systematically analyzed the expression levels of genes that contribute to the execution of autophagy in 21 cancers. Deregulated genes for 21 cancers were analyzed using the level 3 mRNA data from TCGAbiolinks. A total of 574 autophagy genes were mapped to the deregulated genes across 21 cancers. PPI network, cluster analysis, gene enrichment, gene ontology, KEGG pathway, patient survival, protein expression and cMap analysis were performed. Among the autophagy genes, 260 were upregulated, and 43 were downregulated across pan-cancer. The upregulated autophagy genes - CDKN2A and BIRC5 - were the most frequent signatures in cancers and could be universal cancer biomarkers. Significant involvement of autophagy process was found in 8 cancers (CHOL, HNSC, GBM, KICH, KIRC, KIRP, LIHC and SARC). Fifteen autophagy hub genes (ATP6V0C, BIRC5, HDAC1, IL4, ITGB1, ITGB4, MAPK3, mTOR, cMYC, PTK2, SRC, TCIRG1, TP63, TP73 and ULK1) were found to be linked with patients survival and also expressed in cancer patients tissue samples, making them as potential drug targets for these cancers. The deregulated autophagy genes were further used to identify drugs Losartan, BMS-345541, Embelin, Abexinostat, Panobinostat, Vorinostat, PD-184352, PP-1, XMD-1150, Triplotide, Doxorubicin and Ouabain, which could target one or more autophagy hub genes. Overall, our findings shed light on the most frequent cancer-associated autophagy genes, potential autophagy targets and molecules for cancer treatment. These findings can accelerate autophagy modulation in cancer therapy.
Topics: Autophagy; Carcinoma, Hepatocellular; Computational Biology; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Liver Neoplasms; Protein Interaction Maps; Vacuolar Proton-Translocating ATPases
PubMed: 35985410
DOI: 10.1016/j.gene.2022.146821 -
Journal of Experimental & Clinical... Oct 2021Glioblastoma (GBM) has a devastating median survival of only one year. Treatment includes resection, radiation therapy, and temozolomide (TMZ); however, the latter...
BACKGROUND
Glioblastoma (GBM) has a devastating median survival of only one year. Treatment includes resection, radiation therapy, and temozolomide (TMZ); however, the latter increased median survival by only 2.5 months in the pivotal study. A desperate need remains to find an effective treatment.
METHODS
We used the Connectivity Map (CMap) bioinformatic tool to identify candidates for repurposing based on GBM's specific genetic profile. CMap identified histone deacetylase (HDAC) inhibitors as top candidates. In addition, Gene Expression Profiling Interactive Analysis (GEPIA) identified HDAC1 and HDAC2 as the most upregulated and HDAC11 as the most downregulated HDACs. We selected PCI-24781/abexinostat due to its specificity against HDAC1 and HDAC2, but not HDAC11, and blood-brain barrier permeability.
RESULTS
We tested PCI-24781 using in vitro human and mouse GBM syngeneic cell lines, an in vivo murine orthograft, and a genetically engineered mouse model for GBM (PEPG - PTEN; EGFRvIII+; p16 & GFAP Cre +). PCI-24781 significantly inhibited tumor growth and downregulated DNA repair machinery (BRCA1, CHK1, RAD51, and O-methylguanine-DNA- methyltransferase (MGMT)), increasing DNA double-strand breaks and causing apoptosis in the GBM cell lines, including an MGMT expressing cell line in vitro. Further, PCI-24781 decreased tumor burden in a PEPG GBM mouse model. Notably, TMZ + PCI increased survival in orthotopic murine models compared to TMZ + vorinostat, a pan-HDAC inhibitor that proved unsuccessful in clinical trials.
CONCLUSION
PCI-24781 is a novel GBM-signature specific HDAC inhibitor that works synergistically with TMZ to enhance TMZ efficacy and improve GBM survival. These promising MGMT-agnostic results warrant clinical evaluation.
Topics: Animals; Antineoplastic Agents, Alkylating; Cell Line, Tumor; Cell Survival; Computational Biology; DNA Breaks; Disease Management; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Discovery; Drug Resistance, Neoplasm; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mice; Mice, Transgenic; Temozolomide; Transcriptome; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 34696786
DOI: 10.1186/s13046-021-02135-x