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BMC Pulmonary Medicine Feb 2022Exposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that the receptor for advanced glycation end products (RAGE)...
BACKGROUND
Exposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that the receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma. Histone deacetylase (HDAC) has been reported to be important in asthmatic pathogenesis. However, its effect on TDI-induced asthma is not known. The aim of this study was to determine the role of RAGE and HDAC in regulating airway inflammation using a TDI-induced murine asthma model.
METHODS
BALB/c mice were sensitized and challenged with TDI to establish an asthma model. FPS-ZM1 (RAGE inhibitor), JNJ-26482585 and romidepsin (HDAC inhibitors) were administered intraperitoneally before each challenge. In vitro, the human bronchial epithelial cell line 16HBE was stimulated with TDI-human serum albumin (TDI-HSA). RAGE knockdown cells were constructed and evaluated, and MK2006 (AKT inhibitor) was also used in the experiments.
RESULTS
In TDI-induced asthmatic mice, the expression of RAGE, HDAC1, and p-AKT/t-AKT was upregulated, and these expressions were attenuated by FPS-ZM1. Airway reactivity, Th2 cytokine levels in lymph supernatant, IgE, airway inflammation, and goblet cell metaplasia were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by JNJ-26482585 and romidepsin. In addition, JNJ-26482585 and romidepsin ameliorated the redistribution of E-cadherin and β-catenin in TDI-induced asthma. In TDI-HSA-stimulated 16HBE cells, knockdown of RAGE attenuated the upregulation of HDAC1 and phospho-AKT (p-AKT). Treatment with the AKT inhibitor MK2006 suppressed TDI-induced HDAC1 expression.
CONCLUSIONS
These findings indicate that RAGE modulates HDAC1 expression via the PI3K/AKT pathway, and that inhibition of HDAC prevents TDI-induced airway inflammation.
Topics: Animals; Asthma; Benzamides; Cell Line; Cytokines; Depsipeptides; Disease Models, Animal; Histone Deacetylase 1; Humans; Inflammation; Male; Mice; Mice, Inbred BALB C; Phosphatidylinositol 3-Kinases; Receptor for Advanced Glycation End Products; Signal Transduction; Toluene 2,4-Diisocyanate
PubMed: 35148729
DOI: 10.1186/s12890-022-01832-3 -
Molecular Oncology May 2022Cutaneous T-cell lymphomas (CTCLs) are telomerase-positive tumors expressing hTERT, although neither gene rearrangement/amplification nor promoter hotspot mutations...
Cutaneous T-cell lymphomas (CTCLs) are telomerase-positive tumors expressing hTERT, although neither gene rearrangement/amplification nor promoter hotspot mutations could explain the hTERT re-expression. As the hTERT promoter is rich in CpG, we investigated the contribution of epigenetic mechanisms in its re-expression. We analyzed hTERT promoter methylation status in CTCL cells compared with healthy cells. Gene-specific methylation analyses revealed a common methylation pattern exclusively in tumor cells. This methylation pattern encompassed a hypermethylated distal region from -650 to -150 bp and a hypomethylated proximal region from -150 to +150 bp. Interestingly, the hypermethylated region matches with the recently named TERT hypermethylated oncogenic region (THOR). THOR has been associated with telomerase reactivation in many cancers, but it has so far not been reported in cutaneous lymphomas. Additionally, we assessed the effect of THOR on two histone deacetylase inhibitors (HDACi), romidepsin and vorinostat, both approved for CTCL treatment and a DNA methyltransferase inhibitor (DNMTi) 5-azacytidine, unapproved for CTCL. Contrary to our expectations, the findings reported herein revealed that THOR methylation is relatively stable under these epigenetic drugs' pressure, whereas these drugs reduced the hTERT gene expression.
Topics: DNA Methylation; Epigenesis, Genetic; Humans; Lymphoma, T-Cell, Cutaneous; Promoter Regions, Genetic; Telomerase
PubMed: 33715271
DOI: 10.1002/1878-0261.12946 -
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 -
Blood Jan 2018Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were...
Peripheral T-cell lymphomas (PTCL) are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis. Romidepsin and pralatrexate were approved by the US Food and Drug Administration for patients with relapsed/refractory PTCL, exhibiting response rates of 25% and 29% respectively. Based on synergy in preclinical models of PTCL, we initiated a phase 1 study of pralatrexate plus romidepsin in patients with relapsed/refractory lymphoma. This was a single institution dose-escalation study of pralatrexate plus romidepsin designed to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetic profile, and response rates. Patients were treated with pralatrexate (10 to 25 mg/m) and romidepsin (12 to 14 mg/m) on 1 of 3 schedules: every week × 3 every 28 days, every week × 2 every 21 days, and every other week every 28 days. Treatment continued until progression, withdrawal of consent, or medical necessity. Twenty-nine patients were enrolled and evaluable for toxicity. Coadministration of pralatrexate and romidepsin was safe, well tolerated, with 3 DLTs across all schedules (grade 3 oral mucositis × 2; grade 4 sepsis × 1). The recommended phase 2 dose was defined as pralatrexate 25 mg/m and romidepsin 12 mg/m every other week. Twenty-three patients were evaluable for response. The overall response rate was 57% (13/23) across all patients and 71% (10/14) in PTCL. The phase 1 study of pralatrexate plus romidepsin resulted in a high response rate in patients with previously treated PTCL. A phase 2 study in PTCL will determine the efficacy of the combination. This trial was registered at www.clinicaltrials.gov as #NCT01947140.
Topics: Adult; Aged; Aminopterin; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Depsipeptides; Female; Folic Acid Antagonists; Humans; Lymphoma, T-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Young Adult
PubMed: 29141948
DOI: 10.1182/blood-2017-09-806737 -
Clinical Lymphoma, Myeloma & Leukemia Nov 2016Tumor stage and folliculotropic mycosis fungoides are uncommon subtypes of cutaneous T-cell lymphoma (CTCL) with an aggressive disease course. Romidepsin is a histone...
BACKGROUND
Tumor stage and folliculotropic mycosis fungoides are uncommon subtypes of cutaneous T-cell lymphoma (CTCL) with an aggressive disease course. Romidepsin is a histone deacetylase inhibitor approved by the US Food and Drug Administration for patients with CTCL who have received ≥ 1 previous systemic therapy. In the present study, we examined the efficacy and safety of romidepsin in patients from the pivotal, single-arm, open-label, phase II study of relapsed or refractory CTCL with cutaneous tumors and/or folliculotropic disease involvement.
MATERIALS AND METHODS
Patients with CTCL who had received ≥ 1 previous systemic therapy received romidepsin at 14 mg/m on days 1, 8, and 15 of 28-day cycles. Responses were determined by a composite endpoint (assessments of the skin, blood, and lymph nodes). Patients with cutaneous tumors and/or folliculotropic disease involvement were identified by review of diagnosis and histology reports.
RESULTS
The objective response rate to romidepsin was 45% in patients with cutaneous tumors (n = 20) and 60% in patients with folliculotropic disease involvement (n = 10).
CONCLUSION
Romidepsin is active in subtypes of CTCL with less favorable outcomes, such as tumor stage and folliculotropic mycosis fungoides.
Topics: Adult; Aged; Aged, 80 and over; Antibiotics, Antineoplastic; Depsipeptides; Disease Progression; Drug Resistance, Neoplasm; Female; Histone Deacetylase Inhibitors; Humans; Kaplan-Meier Estimate; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Mycosis Fungoides; Recurrence; Treatment Outcome; Young Adult
PubMed: 27637428
DOI: 10.1016/j.clml.2016.08.009 -
SLAS Discovery : Advancing Life... Apr 20223D cell models derived from patient tumors are highly translational tools that can recapitulate the complex genetic and molecular compositions of solid cancers and...
3D cell models derived from patient tumors are highly translational tools that can recapitulate the complex genetic and molecular compositions of solid cancers and accelerate identification of drug targets and drug testing. However, the complexity of performing assays with such models remains a hurdle for their wider adoption. In the present study, we describe methods for processing and multi-functional profiling of tumoroid samples to test compound effects using a novel flowchip system in combination with high content imaging and metabolite analysis. Tumoroids were formed from primary cells isolated from a patient-derived tumor explant, TU-BcX-4IC, that represents metaplastic breast cancer with a triple-negative breast cancer subtype. Assays were performed in a microfluidics-based device (Pu⋅MA System) that allows automated exchange of media and treatments of tumoroids in a tissue culture incubator environment. Multi-functional assay profiling was performed on tumoroids treated with anti-cancer drugs. High-content imaging was used to evaluate drug effects on cell viability and expression of E-cadherin and CD44. Lactate secretion was used to measure tumoroid metabolism as a function of time and drug concentration. Observed responses included loss of cell viability, decrease in E-cadherin expression, and increase of lactate production. Importantly, the tumoroids were sensitive to romidepsin and trametinib, while showed significantly reduced sensitivity to paclitaxel and cytarabine, consistent with the primary tumor response. These methods for multi-parametric profiling of drug effects in patient-derived tumoroids provide an in depth understanding of drug sensitivity of individual tumor types, with important implications for the future development of personalized medicine.
Topics: Antineoplastic Agents; Cadherins; Humans; Lactic Acid; Triple Negative Breast Neoplasms
PubMed: 35124274
DOI: 10.1016/j.slasd.2022.01.006 -
Leukemia & Lymphoma Aug 2016Histone deacetylase (HDAC) inhibitors are epigenetic-modifying agents that have shown promise as anticancer therapies. Several HDAC inhibitors have been approved by the... (Review)
Review
Histone deacetylase (HDAC) inhibitors are epigenetic-modifying agents that have shown promise as anticancer therapies. Several HDAC inhibitors have been approved by the US Food and Drug Administration (FDA) as single-agent therapies to treat T-cell lymphoma. The synergistic combination of HDAC inhibitors with other anticancer agents has the potential to constitute treatment regimens with enhanced efficacy. Romidepsin is a structurally unique, potent, bicyclic class 1 selective HDAC inhibitor approved by the FDA for the treatment of patients with peripheral T-cell lymphoma who have had at least 1 prior therapy and patients with cutaneous T-cell lymphoma who have had at least 1 prior systemic therapy. Here, we review data that support the use of romidepsin in combination with other anticancer agents for the treatment of various malignancies. Promising results have emerged from early clinical studies, supporting the potential for romidepsin combination regimens to constitute safe and effective treatments for cancer.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Depsipeptides; Drug Synergism; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell; Proteasome Inhibitors
PubMed: 27118119
DOI: 10.3109/10428194.2016.1160082 -
OncoTargets and Therapy 2018T-cell lymphoma is a rare hematologic malignancy with an incidence rate between 10% and 20% of that of non-Hodgkin lymphomas. Patients with peripheral T-cell lymphoma... (Review)
Review
T-cell lymphoma is a rare hematologic malignancy with an incidence rate between 10% and 20% of that of non-Hodgkin lymphomas. Patients with peripheral T-cell lymphoma (PTCL) generally have a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy; once relapse occurs, it is mostly regarded as an incurable disease. To overcome the chemorefractoriness of PTCL, several novel agents have been developed. Since the first approval of pralatrexate, a dihydrofolate reductase inhibitor, for relapsed/refractory PTCL by the US Food and Drug Administration, several new agents, such as romidepsin (histone deacetylase inhibitor), brentuximab vedotin (antibody-drug conjugate targeting CD30), chidamide (histone deacetylase inhibitor), and mogamulizumab (anti-CC chemokine receptor 4 monoclonal antibody), have been approved as a therapeutic option for relapsed/refractory PTCL in several countries, including the US, Europe, China, and Japan. Forodesine is a novel, potent purine nucleoside phosphorylase inhibitor that is effective against T-cell malignancies. Although the clinical development of forodesine was discontinued in the US and Europe, a multicenter Phase I/II study of oral forodesine for relapsed PTCL was recently completed in Japan. The overall response rate was 24% (10 of 41 patients), which included four patients with complete response. In general, the toxicity of forodesine is manageable. As the study met the primary end point, forodesine was approved for the treatment of relapsed/refractory PTCL in Japan in March 2017, which was the first approval of forodesine in the world. As forodesine is an oral formulation, it is more convenient than other novel intravenous agents approved for PTCL. However, it is necessary to appropriately manage opportunistic infections and secondary lymphomas possibly associated with long-lasting lymphocytopenia caused by forodesine. In this manuscript, we have summarized the currently available evidence for forodesine and discussed the clinical implications for PTCL treatment.
PubMed: 29719411
DOI: 10.2147/OTT.S140756 -
Microorganisms Sep 2020The human immunodeficiency virus (HIV-1) causes a progressive depletion of CD4+ T cells, hampering immune function. Current experimental strategies to fight the virus... (Review)
Review
The human immunodeficiency virus (HIV-1) causes a progressive depletion of CD4+ T cells, hampering immune function. Current experimental strategies to fight the virus focus on the reactivation of latent HIV-1 in the viral reservoir to make the virus detectable by the immune system, by searching for latency reversal agents (LRAs). We hypothesize that if common molecular pathways elicited by the presence of LRAs are known, perhaps new, more efficient, "shock-and-kill" strategies can be found. Thus, the objective of the present study is to re-evaluate RNA-Seq assays to find differentially expressed genes (DEGs) during latency reversal via transcriptome analysis. We selected six studies (45 samples altogether: 16 negative controls and 29 LRA-treated CD4+ T cells) and 11 LRA strategies through a systematic search in Gene Expression Omnibus (GEO) and PubMed databases. The raw reads were trimmed, counted, and normalized. Next, we detected consistent DEGs in these independent experiments. AZD5582, romidepsin, and suberanilohydroxamic acid (SAHA) were the LRAs that modulated most genes. We detected 948 DEGs shared by those three LRAs. Gene ontology analysis and cross-referencing with other sources of the literature showed enrichment of cell activation, differentiation and signaling, especially mitogen-activated protein kinase () and Rho-GTPases pathways.
PubMed: 33007800
DOI: 10.3390/microorganisms8101505 -
Cell Journal Jan 2019Hemoglobinopathies such as beta-thalassemia and sickle cell disease (SCD) are inherited disorders that are caused by mutations in beta-globin chain. Gamma-globin gene...
OBJECTIVE
Hemoglobinopathies such as beta-thalassemia and sickle cell disease (SCD) are inherited disorders that are caused by mutations in beta-globin chain. Gamma-globin gene reactivation can ameliorate clinical manifestations of betathalassemia and SCD. Drugs that induce fetal hemoglobin (HbF) can be promising tools for treatment of beta-thalassemia and SCD patients. Recently, it has been shown that Simvastatin (SIM) and Romidepsin (ROM) induce HbF. SIM is a BCL11a inhibitor and ROM is a HDAC inhibitor and both of these drugs are Food and Drug Administration (FDA)-approved for hypercholesterolemia and cutaneous T-cell lymphoma respectively. Our aim was to evaluate the synergistic effects of these drugs in inducing HbF.
MATERIALS AND METHODS
In our experimental study, we isolated CD34+ cells from five cord blood samples that were cultured in erythroid differentiation medium containing ROM and Simvastatin. Then Gamma-globin, BCL11a and HDAC gene expression were evaluated on the 7 and 14 day of erythroid differentiation by real-time polymerase chain reaction (PCR) and immunocytochemistry.
RESULTS
Our results showed that combination of SIM and ROM significantly increased Gamma-globin gene expression and inhibit BCL11a and HDAC expression compared to results of using each of them alone. SIM and ROM lead to 3.09- fold increase in HbF production compared to the control group. Also, SIM inhibited BCL11a expression (0.065-fold) and ROM inhibited HDAC1 expression (0.47-fold) as two important inhibitors of HbF production after birth.
CONCLUSION
We propose combination therapy of these drugs may be ameliorate clinical manifestation in beta-thalassemia and SCD with at least side effects and reduce the need for blood transfusion.
PubMed: 30124006
DOI: 10.22074/cellj.2019.5589