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Biomedicine & Pharmacotherapy =... May 2023Endometriosis is a common disease in women and may be one of the factors that induces malignant epithelial ovarian tumors. Previous studies suggested that endometriosis...
Endometriosis is a common disease in women and may be one of the factors that induces malignant epithelial ovarian tumors. Previous studies suggested that endometriosis is related to ARID1A mutation mediating the expression of HDAC6, but the detailed pathogenic mechanism is still unclear. First, we collected endometriosis-associated ovarian carcinoma (EAOC) clinical samples and examined the expression of HDAC6. Our results found that the high HDAC6 expression group was positively correlated with EAOC histology (P = 0.015), stage (P < 0.000), and tumor size (P < 0.000) and inversely correlated with survival (P < 0.000). We also found that ARID1A/HDAC6 induced M2 polarization of macrophages through IL-10. In addition, the HDAC inhibitor (HDACi) vorinostat inhibited cell growth and blocked the effect of HDAC6. Tomographic microscopy was used to monitor the live cell morphology of these treated cells, and we found that vorinostat treatment resulted in substantial cell apoptosis by 3 h 42 min. Next, we established a transgenic mouse model of EAOC and found that vorinostat significantly reduced the size of ovarian tumors by inhibiting M2 macrophage polarization in mice. Together, these data demonstrate that the signaling pathway of E4F1/ARID1A/HDAC6/GATA3 mediates macrophage polarization and provides a novel immune cell-associated therapeutic strategy targeting IL-10 in EAOC.
Topics: Humans; Female; Animals; Mice; Vorinostat; Endometriosis; Interleukin-10; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Carcinoma; Signal Transduction; Macrophages; DNA-Binding Proteins; Transcription Factors; Histone Deacetylase 6; Repressor Proteins
PubMed: 36958195
DOI: 10.1016/j.biopha.2023.114500 -
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 -
British Journal of Haematology Sep 2019
Topics: Adult; B-Lymphocytes; Cladribine; Epigenesis, Genetic; Humans; Lymphoma, Mantle-Cell; Rituximab; Vorinostat
PubMed: 31489625
DOI: 10.1111/bjh.16192 -
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 Clinical Oncology : Official... Nov 2021I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium.
PURPOSE
I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate.
PATIENTS AND METHODS
Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected.
RESULTS
One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%.
CONCLUSION
Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.
Topics: 3-Iodobenzylguanidine; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Infant; Irinotecan; Male; Neoplasm Recurrence, Local; Neuroblastoma; Prognosis; Prospective Studies; Salvage Therapy; Survival Rate; Vincristine; Vorinostat; Young Adult
PubMed: 34270348
DOI: 10.1200/JCO.21.00703 -
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 -
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 -
Cell May 2018BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the...
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.
Topics: Amino Acid Transport System y+; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Humans; MAP Kinase Kinase 1; MAP Kinase Signaling System; Melanoma; Mice; Mutation; Neoplasm Transplantation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Reactive Oxygen Species; Skin Neoplasms; Treatment Outcome; Vorinostat
PubMed: 29754815
DOI: 10.1016/j.cell.2018.04.012