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ACS Omega May 2023Due to the multimodal character of cancer, inhibition of two targets simultaneously by a single molecule is a beneficial and effective approach against cancer. Histone... (Review)
Review
Due to the multimodal character of cancer, inhibition of two targets simultaneously by a single molecule is a beneficial and effective approach against cancer. Histone deacetylase (HDAC) was widely investigated as a novel category of anticancer drug targets due to its crucial role in various biological processes like cell-proliferation, metastasis, and apoptosis. Numerous HDAC inhibitors such as vorinostat and panobinostat are clinically approved but have limited usage due to their low efficacy, nonselectivity, drug resistance, and toxicity. Therefore, HDACs with a dual targeting ability have attracted great attention. The strategy of combining a HDAC inhibitor with other antitumor agents has been proved advantageous for combating the nonselectivity and drug resistivity problems associated with single-target drugs. Henceforth, we have highlighted dual-targeting inhibitors to target HDAC along with topoisomerase, receptor tyrosine kinase inhibitors, and the zeste homolog 2 enzyme. Our Review mainly focuses on the impact of the substituent effect along with the linker variation of well-known HDAC-inhibitor-conjugated anticancer drugs.
PubMed: 37214715
DOI: 10.1021/acsomega.3c00222 -
Frontiers in Microbiology 2021The apicomplexan parasite, , is the most prevalent hemoprotozoan in livestock, causing significant economic losses worldwide. It is essential to develop new and improved...
The apicomplexan parasite, , is the most prevalent hemoprotozoan in livestock, causing significant economic losses worldwide. It is essential to develop new and improved therapeutics, as current control measures are compromised by the development of resistance against the only available antitheilerial drug, buparvaquone (BPQ). Histone deacetylase inhibitors (HDACi) were shown to treat cancer effectively and revealed antiparasitic activity against apicomplexan parasites such as and . In this study, we investigated the antitheilerial activity of the four anti-cancer HDACi (vorinostat, romidepsin, belinostat, and panobinostat) against the schizont stage of parasites. All four HDACi showed potent activity and increased hyperacetylation of the histone-4 protein. However, based on the low host cell cytotoxicity and IC values, vorinostat (0.103 μM) and belinostat (0.069 μM) were the most effective showing antiparasitic activity. The parasite-specific activities of the HDACi (vorinostat and belinostat) were evaluated by western blotting using parasite-specific antibodies and analysis. Both vorinostat and belinostat reduced the infected cell viability by downregulating anti-apoptotic proteins and mitochondrial dysfunction, leading to caspase-dependent cell apoptosis. The HDACi caused irreversible and antiproliferative effects on the infected cell lines. Our results collectively showed that vorinostat and belinostat could be used as an alternative therapy for treating parasites.
PubMed: 34867888
DOI: 10.3389/fmicb.2021.759817 -
Bioorganic Chemistry Sep 2021Hydroxamic acid derivatives constitute an interesting novel class of antitumor agents. Three of them, including vorinostat, are approved drugs for the treatment of...
Hydroxamic acid derivatives constitute an interesting novel class of antitumor agents. Three of them, including vorinostat, are approved drugs for the treatment of malignancies, while several others are currently under clinical trials. In this work, we present new vorinostat analogs containing the benzoxazole ring as the cap group and various linkers. The benzoxazole-based analogs were synthesized starting either from 2-aminobenzoxazole, through conventional coupling, or from benzoxazole, through a metal-free oxidative amination. All the synthesized compounds were evaluated for their antiproliferative activity on three diverse human cancer cell lines (A549, Caco-2 and SF268), in comparison to vorinostat. Compound 12 (GK601), carrying a benzoxazole ring replacement for the phenyl ring of vorinostat, was the most potent inhibitor of the growth of three cell lines (IC 1.2-2.1 μΜ), similar in potency to vorinostat. Compound 12 also inhibited human HDAC1, HDAC2 and HDAC6 like vorinostat. This new analog also showed antiproliferative activity against two colon cancer cell lines genetically resembling pseudomyxoma peritonei (PMP), namely HCT116 GNAS R201C/+ and LS174T (IC 0.6 and 1.4 μΜ, respectively) with potency comparable to vorinostat (IC 1.1 and 2.1 μΜ, respectively).
Topics: Antineoplastic Agents; Benzoxazoles; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Structure-Activity Relationship; Tumor Cells, Cultured; Vorinostat
PubMed: 34229198
DOI: 10.1016/j.bioorg.2021.105132 -
European Journal of Cell Biology Sep 2023ING1 is a chromatin targeting subunit of the Sin3a histone deacetylase (HDAC) complex that alters chromatin structure to subsequently regulate gene expression. We find...
ING1 is a chromatin targeting subunit of the Sin3a histone deacetylase (HDAC) complex that alters chromatin structure to subsequently regulate gene expression. We find that ING1 knockdown increases expression of Twist1, Zeb 1&2, Snai1, Bmi1 and TSHZ1 drivers of EMT, promoting EMT and cell motility. ING1 expression had the opposite effect, promoting epithelial cell morphology and inhibiting basal and TGF-β-induced motility in 3D organoid cultures. ING1 binds the Twist1 promoter and Twist1 was largely responsible for the ability of ING1 to reduce cell migration. Consistent with ING1 inhibiting Twist1 expression in vivo, an inverse relationship between ING1 and Twist1 levels was seen in breast cancer samples from The Cancer Genome Atlas (TCGA). The HDAC inhibitor vorinostat is approved for treatment of multiple myeloma and cutaneous T cell lymphoma and is in clinical trials for solid tumours as adjuvant therapy. One molecular target of vorinostat is INhibitor of Growth 2 (ING2), that together with ING1 serve as targeting subunits of the Sin3a HDAC complex. Treatment with sublethal (LD25-LD50) levels of vorinostat promoted breast cancer cell migration several-fold, which increased further upon ING1 knockout. These observations indicate that correct targeting of the Sin3a HDAC complex, and HDAC activity in general decreases luminal and basal breast cancer cell motility, suggesting that use of HDAC inhibitors as adjuvant therapies in breast cancers that are prone to metastasize may not be optimal and requires further investigation.
Topics: Female; Humans; Breast Neoplasms; Cell Line, Tumor; Chromatin; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Vorinostat
PubMed: 37459799
DOI: 10.1016/j.ejcb.2023.151341 -
Experimental Dermatology Apr 2022Psoriasis is characterized by aberrant activation of several pro-inflammatory circuits as well as abnormal hyperproliferation and dysregulated apoptosis of keratinocytes...
BACKGROUND
Psoriasis is characterized by aberrant activation of several pro-inflammatory circuits as well as abnormal hyperproliferation and dysregulated apoptosis of keratinocytes (KCs). Most currently available therapeutic options primarily target psoriasis-associated immunological defects rather than epidermal abnormalities.
OBJECTIVE
To investigate the efficacy of the histone deacetylase (HDAC) inhibitor, Vorinostat, in targeting hyperproliferation and impaired apoptosis in psoriatic skin.
METHODS
Vorinostat effect was investigated in primary KCs cell cultures using cell cycle analysis by flow cytometry, apoptosis assays (Annexin V-FICH and caspase-3/7) and antibody arrays, qRT-PCR and immunohistochemistry. Vorinostat impact on clinical manifestations of psoriasis was investigated in a chimeric mouse model.
RESULTS
Vorinostat was found to inhibit KCs proliferation and to induce their differentiation and apoptosis. Using a chimeric mouse model, vorinostat was found to result in marked attenuation of a psoriasiform phenotype with a significant decrease in epidermal thickness and inhibition of epidermal proliferation.
CONCLUSIONS
Our results support the notion that vorinostat, a prototypic HDAC inhibitor, may be of potential use in the treatment of psoriasis and other hyperproliferative skin disorders.
Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Histone Deacetylase Inhibitors; Mice; Psoriasis; Vorinostat
PubMed: 34787924
DOI: 10.1111/exd.14502 -
Journal of Cellular Physiology Jan 2021Glioblastoma (GBM) is an aggressive brain tumor and drug resistance remains a major barrier for therapeutics. Epigenetic alterations are implicated in GBM pathogenesis,...
Glioblastoma (GBM) is an aggressive brain tumor and drug resistance remains a major barrier for therapeutics. Epigenetic alterations are implicated in GBM pathogenesis, and epigenetic modulators including histone deacetylase (HDAC) inhibitors are exploited as promising anticancer therapies. Here, we demonstrate that phospholipase D1 (PLD1) is a transcriptional target of HDAC inhibitors and confers resistance to HDAC inhibitor in GBM. Treatment of vorinostat upregulates PLD1 through PKCζ-Sp1 axis. Vorinostat induces dynamic changes in the chromatin structure and transcriptional machinery associated with PLD1 promoter region. Cotreatment of vorinostat with PLD1 inhibitor further attenuates invasion, angiogenesis, colony-forming capacity, and self-renewal capacity, compared with those of either treatment. PLD1 inhibitor overcomes resistance to vorinostat in GBM cells intracranial GBM tumors. Our finding provides new insight into the role of PLD1 as a target of resistance to vorinostat, and PLD1 inhibitor might provide the basis for therapeutic combinations with improved efficacy of HDAC inhibitor.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Chromatin; Drug Resistance, Neoplasm; Epigenomics; Glioblastoma; Histone Deacetylase Inhibitors; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Neovascularization, Pathologic; Phospholipase D; Promoter Regions, Genetic; Transcription, Genetic; U937 Cells; Up-Regulation; Vorinostat
PubMed: 32869317
DOI: 10.1002/jcp.29882 -
Epigenetics & Chromatin May 2023Dynamic chromatin remodeling is associated with changes in the epigenetic pattern of histone acetylations and methylations required for processes based on dynamic...
BACKGROUND
Dynamic chromatin remodeling is associated with changes in the epigenetic pattern of histone acetylations and methylations required for processes based on dynamic chromatin remodeling and implicated in different nuclear functions. These histone epigenetic modifications need to be coordinated, a role that may be mediated by chromatin kinases such as VRK1, which phosphorylates histones H3 and H2A.
METHODS
The effect of VRK1 depletion and VRK1 inhibitor, VRK-IN-1, on the acetylation and methylation of histone H3 in K4, K9 and K27 was determined under different conditions, arrested or proliferating cells, in A549 lung adenocarcinoma and U2OS osteosarcoma cells.
RESULTS
Chromatin organization is determined by the phosphorylation pattern of histones mediated by different types of enzymes. We have studied how the VRK1 chromatin kinase can alter the epigenetic posttranslational modifications of histones by using siRNA, a specific inhibitor of this kinase (VRK-IN-1), and of histone acetyl and methyl transferases, as well as histone deacetylase and demethylase. Loss of VRK1 implicated a switch in the state of H3K9 posttranslational modifications. VRK1 depletion/inhibition causes a loss of H3K9 acetylation and facilitates its methylation. This effect is similar to that of the KAT inhibitor C646, and to KDM inhibitors as iadademstat (ORY-1001) or JMJD2 inhibitor. Alternatively, HDAC inhibitors (selisistat, panobinostat, vorinostat) and KMT inhibitors (tazemetostat, chaetocin) have the opposite effect of VRK1 depletion or inhibition, and cause increase of H3K9ac and a decrease of H3K9me3. VRK1 stably interacts with members of these four enzyme families. However, VRK1 can only play a role on these epigenetic modifications by indirect mechanisms in which these epigenetic enzymes are likely targets to be regulated and coordinated by VRK1.
CONCLUSIONS
The chromatin kinase VRK1 regulates the epigenetic patterns of histone H3 acetylation and methylation in lysines 4, 9 and 27. VRK1 is a master regulator of chromatin organization associated with its specific functions, such as transcription or DNA repair.
Topics: Histones; Chromatin; Protein Processing, Post-Translational; Epigenesis, Genetic
PubMed: 37179361
DOI: 10.1186/s13072-023-00494-7 -
Anti-cancer Drugs Jan 2021T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitors and the synthetic cytotoxic retinoid...
T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitors and the synthetic cytotoxic retinoid fenretinide have achieved durable clinical responses in T-cell lymphomas as single agents, and patients who failed prior HDAC inhibitor treatment have responded to fenretinide. We have previously shown fenretinide synergized with the class I HDAC inhibitor romidepsin in preclinical models of TCLMs. There exist some key differences between HDAC inhibitors. Therefore, we determined if the pan-HDAC inhibitor vorinostat synergizes with fenretinide. We demonstrated cytotoxic synergy between vorinostat and fenretinide in nine TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for non-malignant cells (fibroblasts and blood mononuclear cells). In vivo, vorinostat + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous TCLM xenograft models than other groups. Fenretinide + vorinostat increased reactive oxygen species (ROS, measured by 2',7'-dichlorodihydrofluorescein diacetate dye), resulting in increased apoptosis (via transferase dUTP nick end labeling assay) and histone acetylation (by immunoblotting). The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + vorinostat was abrogated by the antioxidant vitamin C. Like romidepsin, vorinostat combined with fenretinide achieved synergistic cytotoxic activity and increased histone acetylation in preclinical models of TCLMs, but not in non-malignant cells. As vorinostat is an oral agent and not a P-glycoprotein substrate it may have advantages in such combination therapy. These data support conducting a clinical trial of vorinostat combined with fenretinide in relapsed and refractory TCLMs.
Topics: Adolescent; Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Child; Child, Preschool; Drug Synergism; Fenretinide; Humans; Infant, Newborn; Lymphoma, T-Cell; Mice; Mice, Nude; Middle Aged; Prognosis; Reactive Oxygen Species; Tumor Cells, Cultured; Vorinostat; Xenograft Model Antitumor Assays; Young Adult
PubMed: 33079733
DOI: 10.1097/CAD.0000000000001008 -
Research in Veterinary Science Oct 2019To explore the effect of epigenetic modification on the differentiation of goat adipose-derived stem cells in vitro, we used two common epigenetic modification...
To explore the effect of epigenetic modification on the differentiation of goat adipose-derived stem cells in vitro, we used two common epigenetic modification inhibitors, trichostatin A and vorinostat, to treat cashmere goat adipose-derived stem cells and induce adipocyte differentiation. The results showed that trichostatin A and vorinostat changed the relative amounts of H3K9 acetylation and dimethylation in the upstream sequence of PPARG, increased peroxisome proliferator-activated receptor gamma (PPARG) transcription before differentiation and then promoted adipocyte differentiation, and regulated the expression of adipocyte-specific genes. We conclude that adipocyte differentiation is regulated dynamically by different histone modifications. The areas of acetylation and demethylation changed by trichostatin A and vorinostat are the basis for further research on the mechanism of PPARG promoter to regulate adipocytes differentiation and provide research theroies for using adipose-derived stem cells as donor to produce transgenic animals to improve meat quality improvement.
Topics: Acetylation; Adipocytes; Adipogenesis; Animals; Epigenesis, Genetic; Goats; Histone Deacetylase Inhibitors; Hydroxamic Acids; Methylation; PPAR gamma; Promoter Regions, Genetic; Stem Cells; Vorinostat
PubMed: 31610471
DOI: 10.1016/j.rvsc.2019.09.002 -
Genes Jul 2023Cell proliferation and invasion are characteristic of many tumors, including ameloblastoma, and are important features to target in possible future therapeutic...
UNLABELLED
Cell proliferation and invasion are characteristic of many tumors, including ameloblastoma, and are important features to target in possible future therapeutic applications.
OBJECTIVE
The objective of this study was the identification of key genes and inhibitory drugs related to the cell proliferation and invasion of ameloblastoma using bioinformatic analysis.
METHODS
The H10KA_07_38 gene profile database was analyzed by Rstudio and ShinyGO Gene Ontology enrichment. String, Cytoscape-MCODE, and Kaplan-Meier plots were generated, which were subsequently validated by RT-qPCR relative expression and immunoexpression analyses. To propose specific inhibitory drugs, a bioinformatic search using Drug Gene Budger and DrugBank was performed.
RESULTS
A total of 204 significantly upregulated genes were identified. Gene ontology enrichment analysis identified four pathways related to cell proliferation and cell invasion. A total of 37 genes were involved in these pathways, and 11 genes showed an MCODE score of ≥0.4; however, only SLC6A3, SOX10, and LRP5 were negatively associated with overall survival (HR = 1.49 ( = 0.0072), HR = 1.55 ( = 0.0018), and HR = 1.38 ( = 0.025), respectively). The RT-qPCR results confirmed the significant differences in expression, with overexpression of >2 for SLC6A3 and SOX10. The immunoexpression analysis indicated positive LRP5 and SLC6A3 expression. The inhibitory drugs bioinformatically obtained for the above three genes were parthenolide and vorinostat.
CONCLUSIONS
We identify LRP5, SLC6A3, and SOX10 as potentially important genes related to cell proliferation and invasion in the pathogenesis of ameloblastomas, along with both parthenolide and vorinostat as inhibitory drugs that could be further investigated for the development of novel therapeutic approaches against ameloblastoma.
Topics: Humans; Ameloblastoma; Vorinostat; Cell Proliferation; Computational Biology; SOXE Transcription Factors; Low Density Lipoprotein Receptor-Related Protein-5; Dopamine Plasma Membrane Transport Proteins
PubMed: 37628576
DOI: 10.3390/genes14081524