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International Journal of Molecular... Aug 2023Sepsis is a life-threatening medical emergency triggered by excessive inflammation in response to an infection. High mortality rates and limited therapeutic options pose...
Sepsis is a life-threatening medical emergency triggered by excessive inflammation in response to an infection. High mortality rates and limited therapeutic options pose significant challenges in sepsis treatment. Histone deacetylase inhibitors (HDACi), such as suberoylanilide hydroxamic acid (SAHA), have been proposed as potent anti-inflammatory agents for treating inflammatory diseases. However, the underlying mechanisms of sepsis treatment remain poorly understood. In this study, we investigated the effects of SAHA treatment in the lipopolysaccharide (LPS)-induced endotoxemia mouse model as it closely mimics the early stages of the systemic inflammation of sepsis. Our results demonstrate a reduced inflammatory mediator secretion and improved survival rates in mice. Using quantitative acetylomics, we found that SAHA administration increases the acetylation of lactate dehydrogenase (LDHA), and consequently inhibits LDHA activity. Notably, the reduced enzyme activity of LDHA results in a reduced rate of glycolysis. Furthermore, our experiments with bone marrow-derived macrophages (BMDMs) show that SAHA administration reduced oxidative stress and extracellular ATP concentrations, ultimately blunting inflammasome activation. Overall, our study provides insights into the mechanism underlying SAHA's therapeutic effects in sepsis treatment and highlights LDHA as a potential target for developing novel sepsis treatment.
Topics: Animals; Mice; Vorinostat; Histone Deacetylase Inhibitors; Endotoxemia; Hydroxamic Acids; Sepsis
PubMed: 37569823
DOI: 10.3390/ijms241512448 -
Biochemical and Biophysical Research... Sep 2023Calcium overload performs a crucial function in the pathogenesis of myocardial ischemia-reperfusion (I/R) damage, which contributes to mitochondrial impairment and...
Calcium overload performs a crucial function in the pathogenesis of myocardial ischemia-reperfusion (I/R) damage, which contributes to mitochondrial impairment and apoptosis of cardiomyocytes. Suberoylanilide hydroxamic acid (SAHA), a small molecule histone deacetylases inhibitor with modulatory capacity on Na-Ca exchanger (NCX), is proven to have protective potential towards cardiac remodeling and injury, but the mechanism remains unclear. Hence, Hence, our present research explored the modulation of NCX-Ca-CaMKII by SAHA in myocardial I/R damage. Our outcomes indicate that in vitro hypoxia and reoxygenation models of myocardial cells, SAHA treatment inhibited the increase in expression of NCX1, intracellular Ca concentration, expression of CaMKII and self-phosphorylated CaMKII, and cell apoptosis. In addition, SAHA treatment improved myocardial cell mitochondrial swelling inhibited mitochondrial membrane potential diminution and the openness of the mitochondrial permeability transition pore, and protected against mitochondrial dysfunction following I/R injury. In vivo, SAHA treatment alleviated the decrease in FS% and EF%, the increase in the myocardial infarct area, and myocardial enzyme levels caused by I/R injury, while also reducing myocardial cell apoptosis, and inhibiting mitochondrial fission and mitochondrial membrane rupture. These results indicated that SAHA treatment alleviated myocardial cell apoptosis as well as mitochondrial dysfunction resulting from myocardial I/R impairment, and contributed to myocardial function recovery by inhibiting the NCX-Ca-CaMKII pathway. These findings offered additional theoretical support to explore the mechanism of SAHA as a therapeutic agent in cardiac I/R damage and develop new treatment strategies.
Topics: Humans; Vorinostat; Histone Deacetylase Inhibitors; Myocardial Reperfusion Injury; Sodium-Calcium Exchanger; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Myocytes, Cardiac; Apoptosis
PubMed: 37300940
DOI: 10.1016/j.bbrc.2023.05.120 -
Advanced Science (Weinheim,... Aug 2022Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a...
Triple-negative breast cancer (TNBC) exhibits resistance to conventional treatments due to the presence of cancer stem cells (CSCs), causing postsurgical relapse and a dismal prognosis. Umbilical cord blood natural killer (UCB-NK) cell-based immunotherapy represents a promising strategy for cancer treatment. However, its therapeutic efficacy is greatly restrained by downregulation of the NK cell activation ligand MHC class I-related chain A/B (MICA/B) and autophagy-mediated degradation of NK cell-derived granzyme B (GZMB) in CSCs. Herein, it is demonstrated that suberoylanilide hydroxamic acid (SAHA) epigenetically downregulates let-7e-5p and miR-615-3p to increase MICA/B expression and that 3-methyl adenine (3MA) inhibits autophagy-mediated GZMB degradation, thereby sensitizing breast CSCs to UCB-NK cells. Then, an injectable hydrogel is designed to codeliver SAHA and 3MA to enhance UCB-NK cell infusion efficacy in TNBC. The hydrogel precursors can be smoothly injected into the tumor resection bed and form a stable gel in situ, allowing for a pH-sensitive sustained release of SAHA and 3MA. Moreover, UCB-NK cell infusion in combination with the hydrogel efficiently controls postsurgical relapse of TNBC. In addition, the hydrogel exhibits good hemostasis and wound-healing functions. Therefore, the work provides proof of concept that an injectable epigenetic autophagic modulatory hydrogel augments UCB-NK cell therapy to combat postsurgical relapse of TNBC.
Topics: Autophagy; Cell- and Tissue-Based Therapy; Epigenesis, Genetic; Fetal Blood; Humans; Hydrogels; Neoplasm Recurrence, Local; Triple Negative Breast Neoplasms; Vorinostat
PubMed: 35712750
DOI: 10.1002/advs.202201271 -
Investigational New Drugs Jun 2020The majority of patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) harbor a gain of function mutation V617F in Janus kinase (JAK) 2. Although JAK2...
The majority of patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) harbor a gain of function mutation V617F in Janus kinase (JAK) 2. Although JAK2 inhibitors such as ruxolitinib have been shown to be clinically efficacious, the hematological toxicity and eventual drug resistance limit its use as monotherapy. Other gene mutations or dysregulation correlated with the disease phenotype and prognosis have been found to contribute to the complexity and heterogeneity of MPNs, giving rise to an increasing demand for combination therapies. Here, we combine ruxolitinib and the histone deacetylase inhibitor vorinostat as a rational combination strategy for MPNs. We tested the combination of ruxolitinib and vorinostat in cells with the JAK2V617F mutation, such as HEL cells, c-Kit cells from JAK2V617F transgenic mice and bone marrow mononuclear cells (BMMNCs) from patients with MPN. Our results showed significant synergistic effects of this combination strategy. Cotreatment with ruxolitinib and vorinostat synergistically induced apoptosis, cell cycle arrest and inhibition of the colony-forming capacity of HEL cells by attenuating the JAK/signal transducer and activator of transcription (STAT) and protein kinase-B (AKT) signaling pathways. In particular, cotreatment with ruxolitinib and vorinostat prevented the formation of large colonies of colony-forming unit-granulocyte/erythroid/macrophage/megakaryocytes (CFU-GEMMs) and colony-forming unit-granulocyte/macrophages (CFU-GMs) derived from the BMMNCs of patients with MPN. Taken together, these data provided preclinical evidence that the combination of ruxolitinib and vorinostat is a potential dual-target therapy for patients with MPN.
Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Proliferation; Drug Synergism; Histone Deacetylases; Humans; Janus Kinase 2; Macrophages; Mice, Transgenic; Mutation; Myeloid Progenitor Cells; Myeloproliferative Disorders; Neoplasms; Nitriles; Pyrazoles; Pyrimidines; STAT Transcription Factors; Signal Transduction; Vorinostat
PubMed: 31227936
DOI: 10.1007/s10637-019-00794-4 -
PloS One 2022The histone deacetylase (HDAC) inhibitor vorinostat, used with gemcitabine and other therapies, has been effective in treatment of experimental models of pancreatic...
The histone deacetylase (HDAC) inhibitor vorinostat, used with gemcitabine and other therapies, has been effective in treatment of experimental models of pancreatic cancer. In this study, we demonstrated that M344, an HDAC inhibitor, is efficacious against pancreatic cancer in vitro and in vivo, alone or with gemcitabine. By 24 hours post-treatment, M344 augments the population of pancreatic cancer cells in G1, and at a later time point (48 hours) it increases apoptosis. M344 inhibits histone H3 deacetylation and slows pancreatic cancer cell proliferation better than vorinostat, and it does not decrease the viability of a non-malignant cell line more than vorinostat. M344 also elevates pancreatic cancer cell major histocompatibility complex (MHC) class I molecule expression, potentially increasing the susceptibility of pancreatic cancer cells to T cell lysis. Taken together, our findings support further investigation of M344 as a pancreatic cancer treatment.
Topics: Cell Line, Tumor; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Pancreatic Neoplasms; Vorinostat
PubMed: 36126055
DOI: 10.1371/journal.pone.0273518 -
Clinical Lymphoma, Myeloma & Leukemia Mar 2021Outcomes continue to improve in relapsed myeloma as more effective treatment options emerge. We report a multicenter single-arm phase 2 trial evaluating toxicity and...
INTRODUCTION
Outcomes continue to improve in relapsed myeloma as more effective treatment options emerge. We report a multicenter single-arm phase 2 trial evaluating toxicity and efficacy of the histone deacetylase (HDAC) inhibitor vorinostat in combination with bortezomib and dexamethasone.
PATIENTS AND METHODS
Sixteen patients who had received a median of 1 prior treatment line received bortezomib subcutaneously 1.3 mg/m days 1, 4, 8, and 11; dexamethasone 20 mg orally days 1-2, 4-5, 8-9, and 11-12; vorinostat 400 mg orally days 1-4, 8-11, and 15-18 of a 21-day cycle. After receipt of a minimum of 3 cycles of therapy, participants received maintenance vorinostat (400 mg days 1-4 and 15-18 of a 28-day cycle).
RESULTS
Overall response was 81.3%: complete response occurred in 4 of 16, very good partial response in 2 of 16, and partial response 7 of 16. Clinical benefit response rate was 100%; median progression-free survival was 11.9 months. A total of 75% patients experienced a dose reduction or stopped treatment as a result of intolerability.
CONCLUSION
Although toxicity and dose reductions were observed, this study demonstrates that the combination of vorinostat, bortezomib, and dexamethasone is effective in relapsed myeloma with good response rates, suggesting there is an ongoing rationale for further optimization of HDAC inhibitor-based combinations in the treatment of myeloma to improve tolerability and enhance efficacy.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bortezomib; Dexamethasone; Female; Histone Deacetylase Inhibitors; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Multiple Myeloma; Neoplasm Staging; Prognosis; Recurrence; Retreatment; Treatment Outcome; Vorinostat
PubMed: 33478922
DOI: 10.1016/j.clml.2020.11.019 -
The AAPS Journal Aug 2021Bortezomib and vorinostat exhibit synergistic effects in multiple myeloma (MM) cells when given in sequence, and the purpose of this study was to evaluate the molecular...
Bortezomib and vorinostat exhibit synergistic effects in multiple myeloma (MM) cells when given in sequence, and the purpose of this study was to evaluate the molecular determinants of the interaction using a systems pharmacology approach. A Boolean network model consisting of 79 proteins and 225 connections was developed using literature information characterizing mechanisms of drug action and intracellular signal transduction. Network visualization and structural analysis were conducted, and model simulations were compared with experimental data. Critical biomarkers, such as pNFκB, p53, cellular stress, and p21, were identified using measures of network centrality and model reduction. U266 cells were then exposed to bortezomib (3 nM) and vorinostat (2 μM) as single agents or in simultaneous and sequential (bortezomib for first 24 h, followed by addition of vorinostat for another 24 h) combinations. Temporal changes for nine of the critical proteins in the reduced Boolean model were measured over 48 h, and cellular proliferation was measured over 96 h. A mechanism-based systems model was developed that captured the biological basis of a bortezomib and vorinostat sequence-dependent pharmacodynamic interaction. The model was further extended in vivo by linking in vitro parameter values and dynamics of p21, caspase-3, and pAKT biomarkers to tumor growth in xenograft mice reported in the literature. Network-based methodologies and pharmacodynamic principles were integrated successfully to evaluate bortezomib and vorinostat interactions in a mechanistic and quantitative manner. The model can be potentially applied to evaluate their combination regimens and explore in vivo dosing regimens.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Female; Humans; Mice; Models, Biological; Multiple Myeloma; Network Pharmacology; Protein Interaction Maps; Signal Transduction; Systems Analysis; Vorinostat; Xenograft Model Antitumor Assays
PubMed: 34403034
DOI: 10.1208/s12248-021-00622-9 -
Toxicology Aug 2020Vorinostat was approved as the first histone deacetylase inhibitor for the management of cutaneous T cell lymphoma. However, it's in vivo genetic and epigenetic effects...
Vorinostat was approved as the first histone deacetylase inhibitor for the management of cutaneous T cell lymphoma. However, it's in vivo genetic and epigenetic effects on non-cancerous cells remain poorly understood. As genetic and epigenetic changes play a critical role in the pathogenesis of carcinogenesis, we investigated whether vorinostat induces genetic and epigenetic alterations in mouse bone marrow cells. Bone marrow cells were isolated 24 h following the last oral administration of vorinostat at the doses of 25, 50, or 100 mg/kg/day for five days (approximately equal to the recommended human doses). The cells were then used to assess clastogenicity and aneugenicity by the micronucleus test complemented by fluorescence in situ hybridization assay; DNA strand breaks, oxidative DNA strand breaks, and DNA methylation by the modified comet assay; apoptosis by annexin V/PI staining analysis and the occurrence of the hypodiploid DNA content; and DNA damage/repair gene expression by polymerase chain reaction (PCR) Array. The expression of the mRNA transcripts were also confirmed by real-time PCR and western blot analysis. Vorinostat caused structural chromosomal damage, numerical chromosomal abnormalities, DNA strand breaks, oxidative DNA strand breaks, DNA hypomethylation, and programed cell death in a dose-dependent manner. Furthermore, the expression of numerous genes implicated in DNA damage/repair were altered after vorinostat treatment. Accordingly, the genetic/epigenetic mechanism(s) of action of vorinostat may play a role in its carcinogenicity and support the continued study and development of new compounds with lower toxicity.
Topics: Animals; Antineoplastic Agents; Apoptosis; Bone Marrow Cells; Chromosome Aberrations; Comet Assay; DNA Methylation; DNA Repair; Dose-Response Relationship, Drug; Down-Regulation; Male; Mice; Oxidative Stress; Vorinostat
PubMed: 32512035
DOI: 10.1016/j.tox.2020.152507 -
Clinical Cancer Research : An Official... Nov 2020Preclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Preclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma.
PATIENTS AND METHODS
During the dose-escalation study (ClinicalTrials.gov number: NCT01087554) with the HDAC inhibitor vorinostat and the mTOR inhibitor sirolimus (V+S), a patient with Hodgkin lymphoma refractory to nine prior therapies demonstrated a partial response (PR) lasting for 18.5 months, which promoted additional enrollment of patients with Hodgkin lymphoma as well as exploration of an alternative combination of vorinostat and mTOR inhibitor everolimus (V+E).
RESULTS
A total of 40 patients with refractory Hodgkin lymphoma received V+S ( = 22) or V+E ( = 18). Patients received a median of five prior therapies, including brentuximab ( = 39), autologous stem cell transplantation ( = 26), and allogeneic stem cell transplantation ( = 12). The most frequent grade ≥3 treatment-related adverse event was thrombocytopenia in 55% and 67% of patients treated with V+S and V+E, respectively. Complete response was reported in 6 (27%) patients treated with V+S and 2 (11%) patients treated with V+E, and PR was reported in 6 patients (27%) treated with V+S and 4 (22%) patients treated with V+E (objective response rate of 55% and 33%, respectively). In summary, combined HDAC and mTOR inhibition had encouraging activity in heavily pretreated patients with relapsed/refractory Hodgkin lymphoma and warrants further investigation.
CONCLUSIONS
Combined HDAC and mTOR inhibition has salutary activity in patients with relapsed refractory Hodgkin lymphoma and warrants further investigation.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Everolimus; Female; Hematopoietic Stem Cell Transplantation; Histone Deacetylase Inhibitors; Histone Deacetylases; Hodgkin Disease; Humans; Male; Middle Aged; Recurrence; Sirolimus; Stem Cell Transplantation; TOR Serine-Threonine Kinases; Vorinostat; Young Adult
PubMed: 33055173
DOI: 10.1158/1078-0432.CCR-20-1215 -
European Review For Medical and... Feb 2023Breast cancer (BC) is the most common type of cancer in females worldwide. Various approaches were proposed to treat the disease, with no sole agent proved efficient....
OBJECTIVE
Breast cancer (BC) is the most common type of cancer in females worldwide. Various approaches were proposed to treat the disease, with no sole agent proved efficient. Thus, understanding the molecular mechanisms of different drugs became mandatory. The present study aimed at evaluating the role of erlotinib (ERL) and vorinostat (SAHA) in inducing apoptosis in breast cancer cells. The role of these drugs was assessed also on the expression profile of some cancer-related genes; PTEN, P21, TGF, and CDH1.
MATERIALS AND METHODS
In the present study, breast cancer cells (MCF-7) and MDA-MB-231 along with human amniotic cells (WISH) were treated with two concentrations (50, and 100 µM) of erlotinib (ERL) and vorinostat (as known as SAHA) for 24 h. Cells were harvested for downstream analysis. DNA content and apoptosis were analyzed by flow cytometer, and qPCR was performed to assess the expression of different cancer-related genes.
RESULTS
The results indicated that ERL and SAHA arrested both breast cancer cells at the G2/M phase after 24 h compared to normal cells and control. For apoptosis, BC cells showed an elevated level of total apoptosis (early and late) increasing the concentrations of the two applied drugs, with the most effective concentration of ERL at 100 µM in the 24-h treatment. In the control cells, SAHA was proved to be the most effective drug at a concentration of 100 µM with a percentage of apoptosis ranging from 1.7-12% in the 24-h treatment. Necrosis also was dose-dependent in the two breast cancer cell lines used. We further evaluated the expression profiles of PTEN, P21, TGF-β, and CDH1. In MCF-7, data indicated that for TGF-β, PTEN, and P21, the most effective treatment was SAHA at a concentration of 100 µM, while for CDH1, the most effective concentration was ERL at 100 µM. A similar profile was observed in MDA-MB-232, where for TGF-β, PTEN, and P21, the most effective treatment was SAHA at a concentration of 100 µM, while for CDH1, the most effective concentration was SAHA at 50 µM.
CONCLUSIONS
Our results shed some light on the role of ERL and SAHA in regulating the expression of cancer-related genes, though these data need further investigation.
Topics: Female; Humans; Erlotinib Hydrochloride; PTEN Phosphohydrolase; Transcriptional Activation; Up-Regulation; Vorinostat; Breast Neoplasms; Cell Line, Tumor; Cell Cycle Checkpoints
PubMed: 36876690
DOI: 10.26355/eurrev_202302_31391