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Colloids and Surfaces. B, Biointerfaces Sep 2021A combination of photodynamic therapy (PDT) and histone deacetylase inhibitor (HDACis) could potentiate single-mode anti-tumor activity of HDACis or PDT to inhibit tumor...
A combination of photodynamic therapy (PDT) and histone deacetylase inhibitor (HDACis) could potentiate single-mode anti-tumor activity of HDACis or PDT to inhibit tumor relapse and metastasis. However, poor solubility and heterogeneity in cellular uptake and tissue distribution hamper the dual mode antitumor effect. For a controlled drug release of photosensitizers and HDACis in cytoplasm, photosensitizer pyropheophorbide-a (Pyro) encapsulated in polymer polyethylene glycol-b-poly (asparaginyl-vorinostat) (simplified as Pyro@FPPS) are fabricated to achieve their lysosomal spatiotemporal synchronized release. With HDACis modeling PDT in vitro and in vivo, it seems that polymerized Vorinostat encapsulated photosensitizers significantly inhibited the tumor proliferation and metastasis by spatiotemporal synchronized drugs release, and Pyro@FPPS reported here reveals a promising prospect to exert drugs' synergistic effect in a spatiotemporal synchronized manner and can be an effective strategy to inhibit tumor growth, recurrence and metastasis in clinic.
Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Liberation; Histone Deacetylase Inhibitors; Lysosomes; Photochemotherapy; Photosensitizing Agents; Vorinostat
PubMed: 34144323
DOI: 10.1016/j.colsurfb.2021.111903 -
Journal of Biomolecular Structure &... Feb 2020AbbreviationsSAHAsuberoylanilide hydroxamic acidEhHDACHistone Deacetylase from RgRadius of gyrationRMSDroot-mean-square deviationRMSFroot-mean-square...
AbbreviationsSAHAsuberoylanilide hydroxamic acidEhHDACHistone Deacetylase from RgRadius of gyrationRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationMDSmolecular dynamics simulationVMDVisual Molecular DynamicsNAMDNanoscale Molecular DynamicsPBCperiodic boundary conditionsPMEParticle Mesh Ewald3Dthree-dimensionalCαalpha carbonFDAFood and Drug AdministrationnsnanosecondsGPU CUDAGraphics Processing Unit Compute Unified Device ArchitectureCommunicated by Ramaswamy H. Sarma.
Topics: Amebiasis; Entamoeba histolytica; Histone Deacetylases; Metronidazole; Molecular Docking Simulation; Molecular Dynamics Simulation; Phylogeny; Structural Homology, Protein; Trophozoites; Vorinostat
PubMed: 30744531
DOI: 10.1080/07391102.2019.1578693 -
European Journal of Pharmacology May 2020Vorinostat has good therapeutic efficacy against primary cutaneous T-cell lymphoma in the refractory stage. However, the molecular mechanism by which it inhibits solid...
Vorinostat has good therapeutic efficacy against primary cutaneous T-cell lymphoma in the refractory stage. However, the molecular mechanism by which it inhibits solid tumors has not been clarified. To investigate the tumor inhibitory mechanism of vorinostat in cervical cancer, this study used Cell Counting Kit-8, flow cytometry, cell invasion and migration assays and the wound healing assay to evaluate the effects of vorinostat on cervical cancer cell proliferation, apoptosis, cell cycle, migration, and invasion. Real-time quantitative PCR and immunoblotting were used to detect gene and protein expression, respectively, of major histocompatibility class I-related chain A, phosphoinositide 3-kinase, phosphorylated PI3K p55 (Tyr199), and p-Akt (Ser473). The lactate dehydrogenase cytotoxicity assay was used to evaluate the ability of natural killer-92 cells to lyse cervical cancer cells. A xenograft nude mouse model was established to analyze the anti-tumor effect of vorinostat in vivo. Our results showed that vorinostat inhibited the proliferation, migration, and invasion of cervical cancer cells. Vorinostat also induced apoptosis and cell-cycle arrest in the S phase, inhibited PI3K (p110α), p-PI3K p55 (Tyr199), and p-Akt (Ser473) protein expression and upregulated MICA expression in vitro and in vivo, and promoted NK-92 cell-mediated cervical cancer cell lysis. The ability of vorinostat to upregulate MICA expression in cervical cancer cells was related to PI3K/Akt signaling. In brief, vorinostat upregulated MICA through the PI3K/Akt pathway and enhanced the sensitivity of cervical cancer cells to the NK cell-mediated cytolytic reaction. The results of this study demonstrate that vorinostat has anti-solid tumor effects on cervical cancer.
Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Histocompatibility Antigens Class I; Histone Deacetylase Inhibitors; Humans; Killer Cells, Natural; Mice; Neoplasm Invasiveness; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Up-Regulation; Uterine Cervical Neoplasms; Vorinostat; Xenograft Model Antitumor Assays
PubMed: 32135122
DOI: 10.1016/j.ejphar.2020.173057 -
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 -
Transplantation and Cellular Therapy Aug 2022Conditioning regimens play a major role in determining disease outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of i.v....
Vorinostat Combined with Busulfan, Fludarabine, and Clofarabine Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Leukemia: Long-Term Study Outcomes.
Conditioning regimens play a major role in determining disease outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of i.v. busulfan (Bu) as part of conditioning chemotherapy has been shown to be effective in controlling disease relapse; however, disease relapse remains a major cause of death following allo-HSCT. This study was conducted to determine the long-term outcomes of vorinostat with i.v. Bu plus dual nucleoside analogs clofarabine (Clo) and fludarabine (Flu) in the conditioning regimen for patients undergoing allo-HSCT. This was a rapid dose escalation phase I/II study designed to determine whether the addition of vorinostat would improve the efficacy of standard i.v. Bu/Flu/Clo conditioning regimen. This report presents the long-term disease outcomes of this combination in 68 patients with high-risk leukemia, including 31 (46%) with acute lymphoblastic leukemia (ALL) and 37 (54%) with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Fifty-eight patients (85%) were in morphologic complete remission at time of transplantation, and 38 (56%) received a matched unrelated donor graft. Over the median follow-up of 37.6 months, 29 of the 68 patients died (43%), and the nonrelapse mortality (NRM) rate was 22% (n = 15). The median overall survival and median NRM were not reached. Nineteen patients (28%) experienced disease progression. The median progression-free survival was 36.8 months. Thirty-seven patients (57%) developed grade II-IV acute graft-versus-host disease (GVHD), and 20 patients (31%) developed chronic GVHD. Our results suggest a lack of benefit from adding a short course of vorinostat to i.v. Bu/Flu/Clo conditioning regimens for leukemia patients undergoing allo- HSCT.
Topics: Acute Disease; Busulfan; Clofarabine; Drug Therapy, Combination; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Recurrence; Vidarabine; Vorinostat
PubMed: 35618218
DOI: 10.1016/j.jtct.2022.05.021 -
Neuroscience Letters Nov 2021Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental diseases associated with various gene mutations. Previous genetic and clinical...
Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental diseases associated with various gene mutations. Previous genetic and clinical studies reported that ASH1L is a high ASD risk gene identified in human patients. Our recent study used a mouse model to demonstrate that loss of ASH1L in the developing mouse brain was sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory, suggesting that the disruptive ASH1L mutations are the causative drivers leading the human ASD/ID genesis. Using this Ash1L-deletion-induced ASD/ID mouse model, here we showed that postnatal administration of vorinostat (SAHA), a histone deacetylase inhibitor (HDACi), significantly ameliorated both ASD-like behaviors and ID-like cognitive memory deficit. Thus, our study demonstrates that SAHA is a promising reagent for the pharmacological treatment of core ASD/ID behavioral and memory deficits caused by disruptive ASH1L mutations.
Topics: Animals; Autism Spectrum Disorder; Cognitive Dysfunction; DNA-Binding Proteins; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Histone Deacetylase Inhibitors; Histone-Lysine N-Methyltransferase; Humans; Intellectual Disability; Male; Memory; Mice, Knockout; Social Skills; Vorinostat; Mice
PubMed: 34509565
DOI: 10.1016/j.neulet.2021.136241 -
Cancer Science Jan 2020Drug repositioning is an emerging approach to developing novel cancer treatments. Vorinostat is a histone deacetylase inhibitor approved for cancer treatment, but it...
Drug repositioning is an emerging approach to developing novel cancer treatments. Vorinostat is a histone deacetylase inhibitor approved for cancer treatment, but it could attenuate its anticancer activity by activating the mTOR pathway. The HMG-CoA reductase inhibitor fluvastatin reportedly activates the mTOR inhibitor AMP-activated protein kinase (AMPK), and we thought that it would potentiate vorinostat's anticancer activity in renal cancer cells. The combination of vorinostat and fluvastatin induced robust apoptosis and inhibited renal cancer growth effectively both in vitro and in vivo. Vorinostat activated the mTOR pathway, as evidenced by the phosphorylation of ribosomal protein S6, and fluvastatin inhibited this phosphorylation by activating AMPK. Fluvastatin also enhanced vorinostat-induced histone acetylation. Furthermore, the combination induced endoplasmic reticulum (ER) stress that was accompanied by aggresome formation. We also found that there was a positive feedback cycle among AMPK activation, histone acetylation, and ER stress induction. This is the first study to report the beneficial combined effect of vorinostat and fluvastatin in cancer cells.
Topics: Acetylation; Antineoplastic Agents; Apoptosis; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Endoplasmic Reticulum Stress; Fluvastatin; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Neoplasms; Phosphorylation; TOR Serine-Threonine Kinases; Vorinostat
PubMed: 31675763
DOI: 10.1111/cas.14225 -
Neurotoxicity Research Apr 2021Suberoylanilide hydroxamic acid (SAHA/Vorinostat), a potent inhibitor of histone deacetylases (HDACs), is known to possess antidepressant properties. However, the exact...
Suberoylanilide hydroxamic acid (SAHA/Vorinostat), a potent inhibitor of histone deacetylases (HDACs), is known to possess antidepressant properties. However, the exact mechanisms underlying this activity are unknown. In this study, we evaluated the effect of SAHA on the expression of GluN2A, GluN2B (NMDA receptor subunits), (p-)AMPK, and ΔFos proteins which are an integral part of the signal transduction pathways in the brain and also involved in the pathophysiology of depression as well as the mechanism of antidepressant action. We also measured the concentration of malondialdehyde (MDA - a product of lipid peroxidation). The study was carried out in the prefrontal cortex (PFC) and hippocampus (Hp), brain regions implicated in depression. Although SAHA induced changes in the expression of all the proteins and MDA concentration, the effects differed depending on the drug dose, time, and brain structure involved. SAHA reduced MDA concentration and significantly increased p-AMPK protein expression, indicating it may prevent oxidative stress. SAHA also increased the levels of HDAC3 and NMDA subunits (GluN2A and GluN2B), implying it is neuroprotective and may play a crucial role in synaptic plasticity. Moreover, ΔFosB and FosB levels were significantly elevated, suggesting that SAHA may modulate learning and memory processes. Overall, the data indicate that the Hp might play a pivotal role in the mechanism of action of SAHA, hinting at novel mechanisms it play in the antidepressant and neuroprotective effects of SAHA.
Topics: Animals; Antidepressive Agents; Hippocampus; Histone Deacetylase Inhibitors; Male; Mice, Inbred C57BL; Oxidative Stress; Prefrontal Cortex; Signal Transduction; Vorinostat; Mice
PubMed: 33400178
DOI: 10.1007/s12640-020-00317-7 -
Journal of Cancer Research and... 2022Gastric cancer is a common cause of cancer-related death worldwide, and peritoneal dissemination is the most frequent metastatic pattern of gastric cancer. However, the...
BACKGROUND
Gastric cancer is a common cause of cancer-related death worldwide, and peritoneal dissemination is the most frequent metastatic pattern of gastric cancer. However, the treatment of this disease condition remains difficult. It has been demonstrated that intraperitoneal radioimmunotherapy (ipRIT) with Cu-labeled cetuximab (anti-epidermal growth factor receptor antibody; Cu-cetuximab) is a potential treatment for peritoneal dissemination of gastrointestinal cancer in vivo. Recent preclinical and clinical studies have also shown that a histone deacetylase inhibitor, vorinostat, effectively sensitized gastrointestinal cancer to external radiation.
AIM
In the present study, we examined the efficacy of the combined use of vorinostat, as a radiosensitizer during ipRIT with Cu-cetuximab in a peritoneal dissemination mouse model with human gastric cancer NUGC4 cells stably expressing red fluorescent protein.
METHODS
The mouse model was treated by ipRIT with Cu-cetuximab plus vorinostat, each single treatment, or saline (control). Side effects, including hematological and biochemical parameters, were evaluated in similarly treated, tumor-free mice.
RESULTS
Coadministration of ipRIT with Cu-cetuximab + vorinostat significantly prolonged survival compared to control and each single treatment. No significant toxicity signals were observed in all treatment groups.
CONCLUSIONS
Our data suggest that vorinostat is a potentially effective radiosensitizer for use during the treatment of peritoneal dissemination of gastric cancer by ipRIT with Cu-cetuximab.
Topics: Animals; Cell Line, Tumor; Cetuximab; Disease Models, Animal; Histone Deacetylase Inhibitors; Humans; Mice; Radiation-Sensitizing Agents; Radioimmunotherapy; Stomach Neoplasms; Vorinostat
PubMed: 36149139
DOI: 10.4103/jcrt.JCRT_124_20 -
International Journal of Pharmaceutics Apr 2022Photothermal therapy (PTT) is becoming increasing prevalent in clinic for eradicating the primary tumor and improving cancer patients' compliance. However, photothermal...
Photothermal therapy (PTT) is becoming increasing prevalent in clinic for eradicating the primary tumor and improving cancer patients' compliance. However, photothermal resistance and distal metastasis still haunt the tumor treatment with PTT. Herein, on the basis that histone deacetylase acetylase inhibitor (HDACis) could activate the expression of anti-tumor gene and accelerate the differentiation and apoptosis of tumor cells, we propose that HDACis supplementing PTT could overcome those obstacles with appropriate drug-controlled release strategy. Thus, we fabricated a nano-complex of lysosomal activable vorinostat (SAHA) carrier-prodrug encapsulating black phosphorus quantum dots (BPQDs@PPS) to counter those challenges in PTT. With spherical morphology and favorable bio-safety, BPQDs@PPS could release BPQDs and Vorinostat spontaneously in lysosome, not only effectively inhibiting tumor growth, but also reversing tumor thermotolerance and metastasis within a PTT procedure. Especially, both western blot and immunofluorescence analysis validate that Vorinostat enables PTT to reverse tumor thermotolerance and distal metastasis by down-regulation of HSP70 and up-regulation of H3. Therefore, this research not only reveals the mechanism how HDACis supplement PTT in reversing tumor thermotolerance and metastasis, but also provides a promising prospect to upgrade clinical photothermal therapy.
Topics: Cell Line, Tumor; Humans; Lysosomes; Neoplasms; Prodrugs; Thermotolerance; Vorinostat
PubMed: 35202725
DOI: 10.1016/j.ijpharm.2022.121580