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BMC Research Notes Nov 2014Curative treatments for patients with metastatic synovial sarcoma (SS) do not exist, and such patients have a poor prognosis. We explored combinations of...
BACKGROUND
Curative treatments for patients with metastatic synovial sarcoma (SS) do not exist, and such patients have a poor prognosis. We explored combinations of molecularly-targeted and cytotoxic agents to identify synergistic treatment combinations in SS cells.
METHODS
Two SS cell lines (HS-SY-II and SYO-I) were treated with single agents or combinations of molecularly targeted therapies (HDAC inhibitor, vorinostat; mTOR inhibitor, ridaforolimus) and cytotoxic agents. After 72 hours, cell viability was measured using the MTS cell proliferation assay. Combination Indices (CI) were calculated to determine whether each combination was synergistic, additive, or antagonistic. Western Blot analysis assessed alterations in total and phospho-AKT protein levels in response to drug treatment.
RESULTS
We determined the single-agent IC50 for ridaforolimus, vorinostat, doxorubicin, and melphalan in HS-SY-II and SYO-I. Synergism was apparent in cells co-treated with ridaforolimus and vorinostat: CI was 0.28 and 0.63 in HS-SY-II and SYO-I, respectively. Ridaforolimus/doxorubicin and ridaforolimus/melphalan exhibited synergism in both cell lines. An additive effect was observed with combination of vorinostat/doxorubicin in both cell lines. Vorinostat/melphalan was synergistic in HS-SY-II and additive in SYO-I. Western blot analysis demonstrated that ridaforolimus increased pAKT-ser473 levels; this effect was abrogated by vorinostat co-treatment.
CONCLUSIONS
The combination of ridaforolimus and vorinostat demonstrates in vitro synergism in SS. Addition of vorinostat abrogated ridaforolimus-induced AKT activation. Since AKT activation is a possible mechanism of resistance to mTOR inhibitors, adding vorinostat (or another HDAC inhibitor) may be a route to circumvent AKT-mediated resistance to mTOR inhibitors.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Enzyme Activation; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Inhibitory Concentration 50; Melphalan; Molecular Targeted Therapy; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Sarcoma, Synovial; Sirolimus; TOR Serine-Threonine Kinases; Vorinostat
PubMed: 25406429
DOI: 10.1186/1756-0500-7-812 -
Biology of Blood and Marrow... Feb 2019Myeloablative conditioning allogeneic hematopoietic cell transplantation (HCT) puts patients at greater risk for significant cognitive and quality of life decline... (Clinical Trial)
Clinical Trial Comparative Study
Myeloablative conditioning allogeneic hematopoietic cell transplantation (HCT) puts patients at greater risk for significant cognitive and quality of life decline compared with recipients of reduced-intensity conditioning or autologous HCT. Vorinostat, a histone deacetylase inhibitor, has been shown to have neuroprotective and neurorestorative effects in preclinical models of neurologic diseases. Thus, within the context of a myeloablative conditioning phase II clinical trial of vorinostat combined with tacrolimus and methotrexate for graft-versus-host disease prophylaxis, we conducted an ancillary study to evaluate feasibility of assessing associations between vorinostat and neurocognitive function and quality of life (ClinicalTrials.gov NCT02409134). Nine patients (mean age, 53 years; range, 36 to 66) underwent computerized neuropsychological testing (Cogstate) and completed surveys of mood (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), and quality of life (Functional Assessment of Cancer Therapy-General). Control cohorts from a separate concurrent longitudinal study (19 autologous and 18 allogeneic HCT patients, who matched the vorinostat patients on relevant medical and demographic variables) completed the same test battery. All allogeneic patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched unrelated donors. The total neurocognitive performance score of vorinostat patients did not change significantly across the study duration (ie, baseline, day 30, day 100, and day 160). Depression, anxiety, and quality of life also did not differ significantly across time. In univariate analyses (analysis of variance), vorinostat-treated patients showed no difference in neurocognitive function or quality of life compared with autologous and allogeneic control subjects. However, when medical variables were accounted for in a linear mixed effects regression model, the total neurocognitive performance of vorinostat-treated patients was comparable with autologous control subjects. Notably, autologous control subjects performed significantly better than allogeneic control subjects (estimate, .64; standard error, .23; P ≤ .01). Moreover, a smaller percentage of vorinostat-treated patients were classified as mildly, moderately, or severely impaired across neurocognitive domains as well as time points compared with both control cohorts. Thus, vorinostat may have neurorestorative or neuroprotective effects in the HCT setting. Accordingly, we recognize the need for a future, full-scale randomized controlled trial to further examine this hypothesis.
Topics: Adult; Aged; Allografts; Autografts; Cognition; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Neuroprotective Agents; Quality of Life; Transplantation Conditioning; Unrelated Donors; Vorinostat
PubMed: 30244099
DOI: 10.1016/j.bbmt.2018.09.015 -
Aging Jul 2021Originally simply reported to be in a stable and irreversible growth arrest , senescent cells are now clearly associated with normal and pathological ageing . They are...
Originally simply reported to be in a stable and irreversible growth arrest , senescent cells are now clearly associated with normal and pathological ageing . They are characterized by several biomarkers and changes in gene expression that may depend on epigenetic factors, such as histone acetylation, involving a balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, we investigate the expression and the role of HDACs on the senescent phenotype of dermal fibroblasts. We report that during replicative senescence, most canonical HDACs are less expressed. Moreover, treatment with SAHA, a histone deacetylase inhibitor (HDACi) also known as Vorinostat, or the specific downregulation of HDAC2 or HDAC7 by siRNA, induces the appearance of senescence biomarkers of dermal fibroblasts. Conversely, the ectopic re-expression of HDAC7 by lentiviral transduction in pre-senescent dermal fibroblasts extends their proliferative lifespan. These results demonstrate that HDACs expression can modulate the senescent phenotype, highlighting their pharmaceutical interest in the context of healthy ageing.
Topics: Acetylation; Biomarkers; Cellular Senescence; Down-Regulation; Fibroblasts; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Skin; Vorinostat
PubMed: 34253688
DOI: 10.18632/aging.203304 -
Cancer Chemotherapy and Pharmacology Nov 2017This study aimed at recommending pediatric dosages of the histone deacetylase (HDAC) inhibitor vorinostat and potentially more effective adult dosing regimens than the...
A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model of the histone deacetylase (HDAC) inhibitor vorinostat for pediatric and adult patients and its application for dose specification.
PURPOSE
This study aimed at recommending pediatric dosages of the histone deacetylase (HDAC) inhibitor vorinostat and potentially more effective adult dosing regimens than the approved standard dosing regimen of 400 mg/day, using a comprehensive physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling approach.
METHODS
A PBPK/PD model for vorinostat was developed for predictions in adults and children. It includes the maturation of relevant metabolizing enzymes. The PBPK model was expanded by (1) effect compartments to describe vorinostat concentration-time profiles in peripheral blood mononuclear cells (PBMCs), (2) an indirect response model to predict the HDAC inhibition, and (3) a thrombocyte model to predict the dose-limiting thrombocytopenia. Parameterization of drug and system-specific processes was based on published and unpublished in silico, in vivo, and in vitro data. The PBPK modeling software used was PK-Sim and MoBi.
RESULTS
The PBPK/PD model suggests dosages of 80 and 230 mg/m for children of 0-1 and 1-17 years of age, respectively. In comparison with the approved standard treatment, in silico trials reveal 11 dosing regimens (9 oral, and 2 intravenous infusion rates) increasing the HDAC inhibition by an average of 31%, prolonging the HDAC inhibition by 181%, while only decreasing the circulating thrombocytes to a tolerable 53%. The most promising dosing regimen prolongs the HDAC inhibition by 509%.
CONCLUSIONS
Thoroughly developed PBPK models enable dosage recommendations in pediatric patients and integrated PBPK/PD models, considering PD biomarkers (e.g., HDAC activity and platelet count), are well suited to guide future efficacy trials by identifying dosing regimens potentially superior to standard dosing regimens.
Topics: Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Male; Middle Aged; Vorinostat; Young Adult
PubMed: 28988277
DOI: 10.1007/s00280-017-3447-x -
British Journal of Haematology Oct 2015Research has shown that proteasome inhibitors (e.g., carfilzomib), immunomodulatory agents (e.g., lenalidomide), histone deacetylase inhibitors (e.g., vorinostat) and...
Research has shown that proteasome inhibitors (e.g., carfilzomib), immunomodulatory agents (e.g., lenalidomide), histone deacetylase inhibitors (e.g., vorinostat) and corticosteroids (e.g., dexamethasone) have synergistic anti-multiple myeloma (MM) activity. This phase I dose-escalation study evaluated a regimen combining carfilzomib, lenalidomide, vorinostat and dexamethasone (QUAD) in patients with relapsed and/or refractory MM. Seventeen patients received carfilzomib (15, 20, or 20/27 mg/m(2) ; 30-min infusion; days 1, 2, 8, 9, 15, 16), lenalidomide (15 or 25 mg; days 1-21), vorinostat (300 or 400 mg; days 1-7, 15-21), and dexamethasone (40 mg; days 1, 8, 15, 22) in 28-d cycles. No dose-limiting toxicities were observed; the maximum tolerated dose was not reached. The maximum administered dose was carfilzomib 20/27 mg/m(2) , lenalidomide 25 mg, vorinostat 400 mg, and dexamethasone 40 mg. Common grade ≥3 adverse events included neutropenia (53%), thrombocytopenia (53%) and anaemia (41%). The overall response rate was 53%: 12% of patients achieved a very good partial response (PR) and 41% of patients achieved a PR. At a median follow-up of 10 months, median progression-free survival was 12 months and median overall survival was not reached. Treatment with QUAD was feasible and had encouraging activity in patients with relapsed and/or refractory MM.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival; Female; Humans; Hydroxamic Acids; Lenalidomide; Male; Middle Aged; Multiple Myeloma; Oligopeptides; Survival Rate; Thalidomide; Vorinostat
PubMed: 26018491
DOI: 10.1111/bjh.13517 -
Nature Communications Sep 2016The 'shock and kill' approach to cure human immunodeficiency virus (HIV) includes transcriptional induction of latent HIV-1 proviruses using latency-reversing agents... (Clinical Trial)
Clinical Trial
The 'shock and kill' approach to cure human immunodeficiency virus (HIV) includes transcriptional induction of latent HIV-1 proviruses using latency-reversing agents (LRAs) with targeted immunotherapy to purge infected cells. The administration of LRAs (panobinostat or vorinostat) to HIV-1-infected individuals on antiretroviral therapy induces a significant increase in cell-associated unspliced (CA-US) HIV-1 RNA from CD4(+) T cells. However, it is important to discern whether the increases in CA-US HIV-1 RNA are due to limited or broad activation of HIV-1 proviruses. Here we use single-genome sequencing to find that the RNA transcripts observed following LRA administration are genetically diverse, indicating activation of transcription from an extensive range of proviruses. Defective sequences are more frequently found in CA HIV-1 RNA than in HIV-1 DNA, which has implications for developing an accurate measure of HIV-1 reservoir size. Our findings provide insights into the effects of panobinostat and vorinostat as LRAs for latent HIV-1.
Topics: Adult; Anti-HIV Agents; CD4-Positive T-Lymphocytes; DNA, Viral; Drug Administration Schedule; HIV Infections; HIV-1; Humans; Hydroxamic Acids; Indoles; Middle Aged; Panobinostat; RNA, Viral; Viremia; Virus Latency; Vorinostat
PubMed: 27605062
DOI: 10.1038/ncomms12731 -
Cancer Science Feb 2020Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) harboring BIM deletion polymorphism (BIM deletion) have poor responses...
Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) harboring BIM deletion polymorphism (BIM deletion) have poor responses to EGFR TKI. Mechanistically, the BIM deletion induces preferential splicing of the non-functional exon 3-containing isoform over the functional exon 4-containing isoform, impairing TKI-induced, BIM-dependent apoptosis. Histone deacetylase inhibitor, vorinostat, resensitizes BIM deletion-containing NSCLC cells to EGFR-TKI. In the present study, we determined the safety of vorinostat-gefitinib combination and evaluated pharmacodynamic biomarkers of vorinostat activity. Patients with EGFR-mutated NSCLC with the BIM deletion, pretreated with EGFR-TKI and chemotherapy, were recruited. Vorinostat (200, 300, 400 mg) was given daily on days 1-7, and gefitinib 250 mg was given daily on days 1-14. Vorinostat doses were escalated based on a conventional 3 + 3 design. Pharmacodynamic markers were measured using PBMC collected at baseline and 4 hours after vorinostat dose on day 2 in cycle 1. No dose-limiting toxicities (DLT) were observed in 12 patients. We determined 400 mg vorinostat as the recommended phase II dose (RP2D). Median progression-free survival was 5.2 months (95% CI: 1.4-15.7). Disease control rate at 6 weeks was 83.3% (10/12). Vorinostat preferentially induced BIM mRNA-containing exon 4 over mRNA-containing exon 3, acetylated histone H3 protein, and proapoptotic BIM protein in 11/11, 10/11, and 5/11 patients, respectively. These data indicate that RP2D was 400 mg vorinostat combined with gefitinib in BIM deletion/EGFR mutation double-positive NSCLC. BIM mRNA exon 3/exon 4 ratio in PBMC may be a useful pharmacodynamic marker for treatment.
Topics: Aged; Aged, 80 and over; Bcl-2-Like Protein 11; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; ErbB Receptors; Female; Gefitinib; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Sequence Deletion; Survival Analysis; Treatment Outcome; Vorinostat
PubMed: 31782583
DOI: 10.1111/cas.14260 -
BioMed Research International 2020Identifying the potential side effects of drugs is crucial in clinical trials in the pharmaceutical industry. The existing side effect prediction methods mainly focus on... (Comparative Study)
Comparative Study
Identifying the potential side effects of drugs is crucial in clinical trials in the pharmaceutical industry. The existing side effect prediction methods mainly focus on the chemical and biological properties of drugs. This study proposes a method that uses diverse information such as drug-drug interactions from DrugBank, drug-drug interactions from network, single nucleotide polymorphisms, and side effect anatomical hierarchy as well as chemical structures, indications, and targets. The proposed method is based on the assumption that properties used in drug repositioning studies could be utilized to predict side effects because the phenotypic expression of a side effect is similar to that of the disease. The prediction results using the proposed method showed a 3.5% improvement in the area under the curve (AUC) over that obtained when only chemical, indication, and target features were used. The random forest model delivered outstanding results for all combinations of feature types. Finally, after identifying candidate side effects of drugs using the proposed method, the following four popular drugs were discussed: (1) dasatinib, (2) sitagliptin, (3) vorinostat, and (4) clonidine.
Topics: Area Under Curve; Clonidine; Dasatinib; Drug Interactions; Drug Repositioning; Drug-Related Side Effects and Adverse Reactions; Humans; Machine Learning; Polymorphism, Single Nucleotide; Sitagliptin Phosphate; Vorinostat
PubMed: 32190647
DOI: 10.1155/2020/1357630 -
Medicina (Kaunas, Lithuania) Jan 2019Alterations in gene expressions are often due to epigenetic modifications that can have a significant influence on cancer development, growth, and progression. Lately,...
BACKGROUND AND OBJECTIVE
Alterations in gene expressions are often due to epigenetic modifications that can have a significant influence on cancer development, growth, and progression. Lately, histone deacetylase inhibitors (HDACi) such as suberoylanilide hydroxamic acid (SAHA, or vorinostat, MK0683) have been emerging as a new class of drugs with promising therapeutic benefits in controlling cancer growth and metastasis. The small molecule RG7388 (idasanutlin, R05503781) is a newly developed inhibitor that is specific for an oncogene-derived protein called MDM2, which is also in clinical trials for the treatment of various types of cancers. These two drugs have shown the ability to induce p21 expression through distinct mechanisms in MCF-7 and LNCaP cells, which are reported to have wild-type TP53. Our understanding of the molecular mechanism whereby SAHA and RG7388 can induce cell cycle arrest and trigger cell death is still evolving. In this study, we performed experiments to measure the cell cycle arrest effects of SAHA and RG7388 using MCF-7 and LNCaP cells.
MATERIALS AND METHODS
The cytotoxicity, cell cycle arrest, and apoptosis/necroptosis effects of the SAHA and RG7388 treatments were assessed using the Trypan Blue dye exclusion (TBDE) method, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, fluorescence assay with DEVD-amc substrate, and immunoblotting methods.
RESULTS
The RG7388 treatment was able to induce cell death by elevating p21 through inhibition of MDM2 in LNCaP, but not in MCF-7 cells, even though there was evidence of p53 elevation. Hence, we suspect that there is some level of uncoupling of p53-mediated transcriptional induction of p21 in MCF-7 cells.
CONCLUSION
Our results from MCF-7 and LNCaP cells confirmed that SAHA and RG7388 treatments were able to induce cell death via a combination of cell cycle arrest and cytotoxic mechanisms. We speculate that our findings could lead to the development of newer treatments for breast and prostate cancers with drug combinations including HDACi.
Topics: Apoptosis; Breast Neoplasms; Cell Cycle Checkpoints; Cell Survival; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Drug Discovery; Female; Histone Deacetylase Inhibitors; Humans; MCF-7 Cells; Male; Prostatic Neoplasms; Proto-Oncogene Proteins c-mdm2; Pyrrolidines; Tumor Suppressor Protein p53; Vorinostat; para-Aminobenzoates
PubMed: 30700046
DOI: 10.3390/medicina55020030 -
Cancer Biology & Therapy 2019Checkpoint immunotherapy antibodies have not shown efficacy in pancreatic adenocarcinoma. Pre-clinical studies and subsequently an on-going phase I trial have...
Checkpoint immunotherapy antibodies have not shown efficacy in pancreatic adenocarcinoma. Pre-clinical studies and subsequently an on-going phase I trial have demonstrated the safety and efficacy of combinatorial radio-chemotherapy plus surgery in this malignancy, including the combination of sorafenib and vorinostat. The lethality of [sorafenib + vorinostat] was enhanced by gemcitabine. Exposure to [sorafenib + vorinostat] reduced the expression of β-catenin, ERBB1, BCL-XL and MCL-1, and the phosphorylation of AKT T308, AKT S473, GSK3 S9/21, mTORC1 and mTORC2. The drug combination increased the expression of Beclin1 and the phosphorylation of eIF2α S51. The drug combination rapidly reduced the levels of multiple HDAC proteins that was directly associated with the previously noted changes in tumor cell biology, as well as with alterations in the expression of biomarkers predictive for a response to checkpoint inhibitor antibodies. In vivo studies using the PAN02 model in its syngeneic mouse demonstrated that an anti-PD-1 antibody had no impact on tumor growth whereas a transient exposure to [sorafenib + vorinostat] significantly suppressed growth. The combination of [sorafenib + vorinostat] with an anti-PD-1 antibody caused a significant further reduction in tumor growth compared to the drug combination alone. Tumors transiently exposed three weeks earlier to [sorafenib + vorinostat] contained elevated levels of CD8+ cells, M1 macrophages and natural killer cells. Drug exposure plus an anti-PD-1 antibody further significantly enhanced the levels of these immune cells in the tumor. Our data argue for performing a new phase I trial in pancreatic cancer combining immunotherapy with [sorafenib + vorinostat]. Abbreviations: ERK: extracellular regulated kinase; PI3K: phosphatidyl inositol 3 kinase; ca: constitutively active; dn: dominant negative; ER: endoplasmic reticulum; AIF: apoptosis inducing factor; AMPK: AMP-dependent protein kinase; mTOR: mammalian target of rapamycin; JAK: Janus Kinase; STAT: Signal Transducers and Activators of Transcription; MAPK: mitogen activated protein kinase; PTEN: phosphatase and tensin homologue on chromosome ten; ROS: reactive oxygen species; CMV: empty vector plasmid or virus; si: small interfering; SCR: scrambled; IP: immunoprecipitation; VEH: vehicle; HDAC: histone deacetylase.
Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Disease Models, Animal; Drug Screening Assays, Antitumor; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Male; Mice; Pancreatic Neoplasms; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Sorafenib; Vorinostat
PubMed: 30142009
DOI: 10.1080/15384047.2018.1507258