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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 -
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 -
ACS Chemical Neuroscience Sep 2020Chronic stress is the leading cause of memory impairment today. Various stress-based models are being developed for studying cognitive impairment. Repurposing of...
Chronic stress is the leading cause of memory impairment today. Various stress-based models are being developed for studying cognitive impairment. Repurposing of existing drugs in a new pharmacology class is the safest and cheapest option for treatment instead of new drug discovery. Vorinostat (VOR) is the first histone deacetylase (HDAC) inhibitor approved for the treatment of cutaneous T-cell lymphoma by the U.S. FDA. VOR follows the rule of five and is reported to cross the blood-brain barrier. Therefore, we aimed to evaluate the procognitive potential of VOR (25 mg/kg) administered by intraperitoneal (ip) route in a stress-based model of chronic corticosterone (CORT) injections (20 mg/kg, subcutaneously (sc)). The study comprised six groups. Normal mice were administered vehicle (VEH) (days 1-21, sc) in the first group, VOR (days 8-21, 25 mg/kg, ip) in the second group, and fluoxetine (FLX) (days 8-21, 15 mg/kg, oral) in the third group. Mice in the remaining three groups were given 20 mg/kg (sc) CORT for 21 days, and VOR (days 8-21, 25 mg/kg, ip) or FLX (days 8-21, 15 mg/kg, oral) was additionally administered to the treatment groups. Behavioral tests such as Morris water maze test, novel object recognition test, and object in place test were performed at the end of the dosing schedule to assess cognition. After behavior tests, mice were sacrificed, and hippocampus was separated from brain tissue for reverse transcriptase polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry studies. VOR treatment attenuated endoplasmic reticulum (ER) stress in CORT mice as evident from the reduction in DNA damage-inducible transcript 3 () (gene encoding CHOP), caspase 12 (), and calpain-2 () mRNA levels, and cleaved caspase 3 (CASP3) protein expression. Bax inhibitor-1 (BI-1) was significantly increased in VOR-treated CORT mice. VOR also reversed CORT induced increase in HDAC2 level in the CA3 region. The protective effects of VOR were comparable to that of FLX in CORT mice. Thus, VOR has the potential to reverse cognitive dysfunction via modulation of ER stress markers and HDAC2.
Topics: Animals; Cognition; Corticosterone; Endoplasmic Reticulum Stress; Fluoxetine; Hippocampus; Mice; Vorinostat
PubMed: 32673474
DOI: 10.1021/acschemneuro.0c00315 -
Drug Development Research May 2023Hypoxia is a characteristic feature of solid tumors, including oral squamous cell carcinoma (OSCC), which causes therapeutic resistance. The hypoxia-inducible factor...
Hypoxia is a characteristic feature of solid tumors, including oral squamous cell carcinoma (OSCC), which causes therapeutic resistance. The hypoxia-inducible factor 1-alpha (HIF-1α) is a key regulator of hypoxic tumor microenvironment (TME) and a promising therapeutic target against solid tumors. Among other HIF-1α inhibitors, vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor (HDACi) targeting the stability of HIF-1α, and PX-12 (1-methylpropyl 2-imidazolyl disulfide) is a thioredoxin-1 (Trx-1) inhibitor preventing accumulation of HIF-1α. HDACis are effective against cancers; however, they are accompanied by several side effects along with an emerging resistance against it. This can be overcome by using HDACi in a combination regimen with Trx-1 inhibitor, as their inhibitory mechanisms are interconnected. HDACis inhibit Trx-1, leading to an increase in the production of reactive oxygen species (ROS) and inducing apoptosis in cancer cells; thus, the efficacy of HDACi can be elevated by using a Trx-1 inhibitor. In this study, we have tested the EC50 (half maximal effective concentration) doses of vorinostat and PX-12 on CAL-27 (an OSCC cell line) under both normoxic and hypoxic conditions. The combined EC50 dose of vorinostat and PX-12 is significantly reduced under hypoxia, and the interaction of PX-12 with vorinostat was evaluated by combination index (CI). An additive interaction between vorinostat and PX-12 was observed in normoxia, while a synergistic interaction was observed under hypoxia. This study provides the first evidence for vorinostat and PX-12 synergism under hypoxic TME, at the same time highlighting the therapeutically effective combination of vorinostat and PX-12 against OSCC in vitro.
Topics: Humans; Vorinostat; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; Mouth Neoplasms; Histone Deacetylase Inhibitors; Head and Neck Neoplasms; Hypoxia; Disulfides; Cell Line, Tumor
PubMed: 36808757
DOI: 10.1002/ddr.22045 -
Journal For Immunotherapy of Cancer Jan 2020The monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer....
BACKGROUND
The monoclonal antibody (mAb) trastuzumab is part of the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer. Antibody-dependent cell-mediated phagocytosis (ADCP) and cytotoxicity (ADCC) are major mechanisms of action of the mAb trastuzumab. Histone deacetylase inhibitors (HDACi), such as valproic acid (VPA) or vorinostat (SAHA), exert several immunostimulatory properties, which contribute at least in part to their anticancer effect. However, the impact of HDACi-induced immunostimulatory effects on trastuzumab-mediated anti-tumor immune response is not well characterized.
METHODS
We analyzed the ADCP and ADCC activity of peripheral blood mononuclear cells (PBMCs) from age and gender-matched healthy volunteers (n=5) against HDACi-treated HER2-overexpressing breast cancer cells (SKBR3), using a well-established in vitro three-color imaging flow cytometry and flow cytometry approach.
RESULTS
VPA and SAHA enhanced trastuzumab-mediated ADCP and trastuzumab-independent cytotoxicity. Mechanistically, VPA upregulated the activating antibody-binding receptor Fc-gamma receptor (FcγR) IIA (CD32A) on monocytes (CD14+). Moreover, VPA and SAHA downregulated the anti-apoptotic protein myeloid leukemia cell differentiation 1 (MCL1) in breast cancer cells. Additionally, VPA and SAHA induced an immunogenic cell death, characterized by the exposure of calreticulin (CALR), as well as decreased the "do not eat me" signal CD47 on tumor cells.
CONCLUSIONS
HDACi VPA and SAHA increase trastuzumab-mediated phagocytosis and trastuzumab-independent cytotoxicity. The immunomodulatory activities of those HDACi support a rationale combined treatment approach with mAb for cancer treatment.
Topics: Antibody-Dependent Cell Cytotoxicity; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Case-Control Studies; Cell Line, Tumor; Drug Synergism; Female; Histone Deacetylase Inhibitors; Humans; Phagocytosis; Prognosis; Receptor, ErbB-2; Receptors, IgG; Trastuzumab; Valproic Acid; Vorinostat
PubMed: 31940587
DOI: 10.1136/jitc-2019-000195 -
Journal of Clinical Oncology : Official... Aug 2017
Topics: Azacitidine; Humans; Lenalidomide; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; United States; Vorinostat
PubMed: 28548890
DOI: 10.1200/JCO.2017.73.0812 -
Leukemia Research Feb 2019
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cohort Studies; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Sorafenib; Vorinostat
PubMed: 30626561
DOI: 10.1016/j.leukres.2018.12.011 -
The Journal of Organic Chemistry Jun 2021Chalaniline B [1-anilino-2,8-dihydroxy-3-(hydroxymethyl)xanthone], an antibiotic previously isolated from vorinostat-treated sp., was prepared in 7 steps from...
Chalaniline B [1-anilino-2,8-dihydroxy-3-(hydroxymethyl)xanthone], an antibiotic previously isolated from vorinostat-treated sp., was prepared in 7 steps from 2-hydroxyxanthone by a route incorporating regioselective oxidative transformations (bromination at C1/C3, ketone directed Pd(II)-catalyzed hydroxylation at C8), installation of the C1-anilino moiety by a regioselective Buchwald-Hartwig amination reaction from 1,3-dibromo-2,8-dimethoxyxanthone, and late-stage hydroxymethylation at C3 using a Stille cross-coupling. Biological evaluation of deshydroxymethylchalaniline B (1-anilino-2,8-dihydroxyxanthone) revealed MIC values of 8 μg mL (25 μM) against both methicillin resistant and .
Topics: Aniline Compounds; Anti-Bacterial Agents; Fungi; Heterocyclic Compounds, 3-Ring; Methicillin-Resistant Staphylococcus aureus; Vorinostat
PubMed: 34000192
DOI: 10.1021/acs.joc.1c00528 -
Experimental Parasitology Mar 2020Safety precautions prior to contact lens usage is essential for preventing Acanthamoeba keratitis. Contact lens disinfecting solutions containing 3% hydrogen peroxide...
Safety precautions prior to contact lens usage is essential for preventing Acanthamoeba keratitis. Contact lens disinfecting solutions containing 3% hydrogen peroxide (HO) are known to exert amoebicidal effect against Acanthamoeba. Yet, these solutions need to be neutralized to prevent ocular irritation, which consequently may result in incomplete disinfection. In this study, amoebicidal effect of tert-butyl hydroperoxide (tBHP) was investigated and its efficacy was compared to those of hydrogen peroxide (HO). HO and tBHP showed dose dependent amoebicidal effect, however high concentration of these compounds demonstrated cytotoxicity in human corneal epithelial (HCE) cells. To reduce their cytotoxicity, the concentrations of both compounds were diluted to 50 μM and subsequently combined with 10 μM vorinostat to enhance amoebicidal effect. Addition of vorinostat induced high amoebicidal effect against Acanthamoeba trophozoites, even at low concentrations of HO or tBHP. Cellular damage induced by combined treatment of HO or tBHP with vorinostat in Acanthamoeba were determined by assessing cell cycle arrest and apoptosis via FACS analysis. While 50 μM HO combined with 10 μM vorinostat showed 36.26% cytotoxicity on HCE cells during 24 h exposure, 50 μM tBHP with 10 μM vorinostat did not show cytotoxicity on HCE cells. These findings suggest that the application of tBHP and vorinostat for Acanthamoeba keratitis treatment and contact lens disinfection system is highly plausible.
Topics: Acanthamoeba; Anti-Infective Agents, Local; Antiprotozoal Agents; Apoptosis; Cell Cycle Checkpoints; Cells, Cultured; Cornea; DNA, Protozoan; Drug Combinations; Epithelial Cells; Humans; Hydrogen Peroxide; Vorinostat; tert-Butylhydroperoxide
PubMed: 31935358
DOI: 10.1016/j.exppara.2020.107833 -
Bone Dec 2013
Topics: Animals; Bone Resorption; Cell Differentiation; Humans; Hydroxamic Acids; Male; Osteoblasts; Vorinostat
PubMed: 23973558
DOI: 10.1016/j.bone.2013.08.019