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Pharmacogenomics Nov 2016The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase... (Review)
Review
The histone deacetylase inhibitor valproic acid (VPA) has been used for many decades in neurology and psychiatry. The more recent introduction of the histone deacetylase inhibitors (HDIs) belinostat, romidepsin and vorinostat for treatment of hematological malignancies indicates the increasing popularity of these agents. Belinostat, romidepsin and vorinostat are metabolized or transported by polymorphic enzymes or drug transporters. Thus, genotype-directed dosing could improve pharmacotherapy by reducing the risk of toxicities or preventing suboptimal treatment. This review provides an overview of clinical studies on the effects of polymorphisms on the pharmacokinetics, efficacy or toxicities of HDIs including belinostat, romidepsin, vorinostat, panobinostat, VPA and a number of novel compounds currently being tested in Phase I and II trials. Although pharmacogenomic studies for HDIs are scarce, available data indicate that therapy with belinostat (UGT1A1), romidepsin (ABCB1), vorinostat (UGT2B17) or VPA (UGT1A6) could be optimized by upfront genotyping.
Topics: Depsipeptides; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Indoles; Panobinostat; Pharmacogenetics; Sulfonamides; Valproic Acid; Vorinostat
PubMed: 27767376
DOI: 10.2217/pgs-2016-0113 -
Neuro-oncology Apr 2022A phase I/II trial of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor, was conducted in children with newly diagnosed diffuse...
BACKGROUND
A phase I/II trial of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor, was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) through the Children's Oncology Group (COG) to: 1) determine the recommended phase II dose (RP2D) of vorinostat given concurrently with radiation therapy; 2) document the toxicities of continuing vorinostat as maintenance therapy after radiation; and 3) to determine the efficacy of this regimen by comparing the risk of progression or death with a historical model from past COG trials.
METHODS
Vorinostat was given once daily, Monday through Friday, during radiation therapy (54 Gy in 30 fractions), and then continued at 230 mg/m2 daily for a maximum of twelve 28-day cycles.
RESULTS
Twelve patients enrolled in the phase I study; the RP2D of vorinostat given concurrently with radiation was 230 mg/m2/day, Monday through Friday weekly. The six patients enrolled at the RP2D and an additional 64 patients enrolled in the phase II study contributed to the efficacy assessment. Although vorinostat was well-tolerated, did not interrupt radiation therapy, and was permanently discontinued in only 8.6% of patients due to toxicities, risk for EFS-event was not significantly reduced compared with the target risk derived from historical COG data (P = 0.32; 1-sided). The 1-year EFS was 5.85% (95% CI 1.89-13.1%) and 1-year OS was 39.2% (27.8-50.5%).
CONCLUSIONS
Vorinostat given concurrently with radiation followed by vorinostat monotherapy was well tolerated in children with newly diagnosed DIPG but failed to improve outcome.
Topics: Astrocytoma; Brain Stem Neoplasms; Child; Diffuse Intrinsic Pontine Glioma; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Vorinostat
PubMed: 34347089
DOI: 10.1093/neuonc/noab188 -
Drug Delivery Dec 2021PD-1/PD-L1 blocking therapy has become one of the most promising methods in the field of tumor treatment. However, it encounters the challenge of immune escape due to...
PD-1/PD-L1 blocking therapy has become one of the most promising methods in the field of tumor treatment. However, it encounters the challenge of immune escape due to the exhaustion of T cells. Studies have shown that the epigenetic regulation drug histone deacetylase inhibitor (HDACi) may be able to reverse exhausted T cells by changing the epigenetic transcription program. Therefore, the combination of epigenetic therapy and PD-1/PD-L1 blockade therapy is expected to reverse the immune escape, whereas the overriding goal should aim at the spontaneous release and synergy of PD-1/PD-L1 blocking siRNA and HDACi. In this study, we develop PDDS{polyethylene glycol-b-asparaginate(diethylenetriamine-vorinostat), (PEG-b-P[Asp(DET-SAHA)] PPDS)}encapsulating siRNA-PD-L1to provide micelles siRNA-PD-L1-loaded micelles (siRNA@PPDS). Transmission electron microscope (TEM) images demonstrate that siRNA@PPDS micelles presented spherical morphology with a size of about 120 nm; hydrodynamic data analysis indicates pH sensitivity of siRNA@PPDS micelles. The experiments reveal that siRNA@PPDS micelles could be well uptaken by the tumor cells to silence the expression of PD-L1 protein in a dose-dependent manner; compared with the free SAHA, the SAHA-loaded micelles PPDS show higher cytotoxicity to induce tumor cell apoptosis and block cell cycle in G1 phase on melanoma-bearing mice, siRNA@PPDS has shown outstanding inhibition of tumor growth and pulmonary metastasis. By comprehensively activating the immune system, lysosome activable polymeric vorinostat encapsulating PD-L1KD for the combination therapy of PD-L1-KD and HDACIs can be an effective strategy to reverse the unresponsiveness of immune checkpoint inhibitors and a promising treatment to inhibit tumor growth, recurrence, and metastasis in clinic.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Survival; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Drug Carriers; Drug Liberation; Epigenesis, Genetic; G1 Phase; Histone Deacetylase Inhibitors; Hydrogen-Ion Concentration; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Micelles; Microscopy, Electron, Transmission; Particle Size; Polyethylene Glycols; Programmed Cell Death 1 Ligand 2 Protein; RNA, Small Interfering; Vorinostat; Xenograft Model Antitumor Assays
PubMed: 34036867
DOI: 10.1080/10717544.2021.1927246 -
BMC Microbiology Feb 2020Invasive aspergillosis is a fungal infection that occurs mainly in immunocompromised patients. It is responsible for a high degree of mortality and is invariably...
BACKGROUND
Invasive aspergillosis is a fungal infection that occurs mainly in immunocompromised patients. It is responsible for a high degree of mortality and is invariably unresponsive to conventional antifungal treatments. Histone deacetylase inhibitors can affect the cell cycle, apoptosis and differentiation. The histone deacetylase inhibitor vorinostat (SAHA) has recently received approval for the treatment of cutaneous T cell lymphoma. Here, we investigated the interactions of SAHA and itraconazole, voriconazole, and posaconazole against Aspergillus spp. in vitro using both planktonic cells and biofilms.
RESULTS
We investigated 20 clinical strains using broth microdilution checkerboard methods. The results showed synergy between SAHA and itraconazole, voriconazole, and posaconazole against 60, 40, and 25% of tested isolates of planktonic Aspergillus spp., respectively. Similar synergy was also observed against Aspergillus biofilms. The expression of the azole-associated multidrug efflux pumps MDR1, MDR2, MDR3 and MDR4, as well as that of HSP90, was measured by RT-PCR. The results indicated that the molecular mechanism of the observed synergistic effects in Aspergillus fumigatus may be partly associated with dampened expression of the efflux pump genes and, furthermore, that HSP90 suppression may be a major contributor to the observed synergistic effects of the drugs.
CONCLUSIONS
SAHA has potential as a secondary treatment to enhance the effects of azoles against both biofilm and planktonic cells of Aspergillus spp. in vitro. This effect occurs mostly by inhibition of HSP90 expression.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Aspergillus; Azoles; Biofilms; Drug Synergism; Gene Expression Regulation; HSP90 Heat-Shock Proteins; Itraconazole; Microbial Sensitivity Tests; Plankton; Triazoles; Voriconazole; Vorinostat; ATP-Binding Cassette Sub-Family B Member 4
PubMed: 32028887
DOI: 10.1186/s12866-020-1718-x -
Oncoimmunology Sep 2020Neuroblastoma is a childhood malignancy and in the majority of patients, the primary tumor arises in one of the adrenal glands. Neuroblastoma cells highly express the...
Neuroblastoma is a childhood malignancy and in the majority of patients, the primary tumor arises in one of the adrenal glands. Neuroblastoma cells highly express the disialoganglioside GD2, which is the primary target for the development of neuroblastoma immunotherapy. Anti-GD2 mAbs have shown clinical efficacy and are integrated into standard treatment for high-risk neuroblastoma patients. We previously reported synergy between the HDAC inhibitor Vorinostat and anti-GD2 mAbs in a heterotopic, subcutaneous growing neuroblastoma model. Additionally, we have previously developed an orthotopic intra-adrenal neuroblastoma model showing more aggressive tumor growth. Here, we report that anti-GD2 mAb and Vorinostat immunocombination therapy is even more effective in suppressing neuroblastoma growth in the aggressive orthotopic model, resulting in increased animal survival. Intra-adrenal tumors from mice treated with Vorinostat were highly infiltrated with myeloid cells, including macrophages, displaying increased MHCII and Fc-receptor expression. Collectively, these data provide a strong rationale for clinical testing of anti-GD2 mAbs with concomitant Vorinostat in neuroblastoma patients.
Topics: Animals; Antibodies, Monoclonal; Child; Gangliosides; Humans; Immunotherapy; Mice; Neuroblastoma; Vorinostat
PubMed: 33457098
DOI: 10.1080/2162402X.2020.1817653 -
Archiv Der Pharmazie Sep 2023Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the...
Anticancer drug conjugates are an emerging approach for future cancer treatment. Here, we report a series of hybrid ligands merging the neurohormone melatonin with the approved histone deacetylase (HDAC) inhibitor vorinostat, using melatonin's amide side chain (3a-e), its indolic nitrogen (5a-d), and its ether oxygen (7a-d) as attachment points. Several hybrid ligands showed higher potency thanvorinostat in both HDAC inhibition and cellular assays on different cultured cancer cell lines. In the most potent HDAC1 and HDAC6 inhibitors, 3e, 5c, and 7c, the hydroxamic acid moiety of vorinostat is linked to melatonin through a hexamethylene spacer. Hybrid ligands 5c and 7c were also found to be potent growth inhibitors of MCF-7, PC-3M-Luc, and HL-60 cancer cell lines. As these compounds showed only weak agonist activity at melatonin MT receptors, the findings indicate that their anticancer actions are driven by HDAC inhibition.
Topics: Vorinostat; Histone Deacetylases; Melatonin; Ligands; Structure-Activity Relationship; Histone Deacetylase Inhibitors; Antineoplastic Agents; Hydroxamic Acids; Cell Line, Tumor; Cell Proliferation; Histone Deacetylase 1; Histone Deacetylase 6; Neoplasms
PubMed: 37339785
DOI: 10.1002/ardp.202300149 -
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 -
Neoplasia (New York, N.Y.) Aug 2021ONC201/TIC10 activates TRAIL signaling through ATF4 and the integrated stress response (ISR). ONC201 demonstrated tumor regressions and disease stability in patients...
EZH2i EPZ-6438 and HDACi vorinostat synergize with ONC201/TIC10 to activate integrated stress response, DR5, reduce H3K27 methylation, ClpX and promote apoptosis of multiple tumor types including DIPG.
ONC201/TIC10 activates TRAIL signaling through ATF4 and the integrated stress response (ISR). ONC201 demonstrated tumor regressions and disease stability in patients with histone H3K27M-mutated midline-glioma. H3K27M-mutation prevents H3K27-methylation on the mutated allele. EZH2 inhibitors (EZH2i) reduce H3K27 methylation and have anti-tumor effects. We hypothesized ONC201 sensitivity and tumor apoptosis may increase by reducing H3K27-methylation with EZH2i or HDACi as mimics of H3K27M-mutation. EZH2i EPZ-6438 (tazemetostat) or PF-06821497 and HDACi vorinostat were combined with ONC201 to treat multiple cancer cell lines and cell viability and histone modifications were analyzed. We observed synergistic effects towards cell viability in multiple cancers by EPZ-6438 or PF-06821497 plus ONC201 or triple therapy with vorinostat, EPZ-6438, and ONC201. EPZ-6438 and vorinostat synergized with ONC201 to enhance apoptosis. Activation of the ISR and TRAIL-DR5 were observed in cells treated with ONC201 -/+ epigenetic modulators. Knockdown of ATF4 reduced DR5 induction and apoptosis following EZH2i and ONC201 treatment of U251 glioma cells. mRNA expression of dopamine-receptors did not correlate with ONC201 sensitivity in the tumor cell lines tested (N = 12), including changes after epigenetic drugs. Dopamine did not rescue apoptosis by ONC201 in different tumor cell lines (N = 10) including 2 GBM, 3 DIPG and did not prevent DR5 activation or apoptosis. DRD2 agonist sumanirole did not protect brain tumor cells (N = 6 including 4 DIPG cell lines) from ONC201 reduction in viability. Although synergy was observed with ONC201 and vorinostat, there was no significant increase in H3K27 acetylation in cell lines including DIPG as compared to vorinostat alone, and in some cases the acetylation was less than vorinostat alone at 72 H. H3K27 methylation reduction correlated with synergy from combinations of either EPZ-6438 or vorinostat with ONC201 or triple combination. Our findings provide a rationale for combination of ONC201 and epigenetic modulators including triple therapy for in vivo and clinical testing in treatment of human malignancies including brain tumors and DIPG.
Topics: Antineoplastic Agents; Apoptosis; Benzamides; Biphenyl Compounds; Cell Line, Tumor; Cell Survival; Drug Synergism; Endopeptidase Clp; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histones; Humans; Imidazoles; Methylation; Morpholines; Pyridines; Pyridones; Pyrimidines; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; Stress, Physiological; TNF-Related Apoptosis-Inducing Ligand; Vorinostat
PubMed: 34246076
DOI: 10.1016/j.neo.2021.06.007 -
British Journal of Haematology Sep 2019
Topics: Adult; B-Lymphocytes; Cladribine; Epigenesis, Genetic; Humans; Lymphoma, Mantle-Cell; Rituximab; Vorinostat
PubMed: 31489625
DOI: 10.1111/bjh.16192 -
European Journal of Pharmaceutical... Jan 2022Vorinostat (suberoylanilide hydroxamic acid, SAHA), an FDA-approved drug for cutaneous T cell lymphoma, has antiangiogenic and anti-inflammatory activity and thus has...
Improving the solubility of vorinostat using cyclodextrin inclusion complexes: The physicochemical characteristics, corneal permeability and ocular pharmacokinetics of the drug after topical application.
Vorinostat (suberoylanilide hydroxamic acid, SAHA), an FDA-approved drug for cutaneous T cell lymphoma, has antiangiogenic and anti-inflammatory activity and thus has therapeutic potential for inflammatory corneal neovascularization (CNV). However, its practical administration is limited due to its poor aqueous solubility and permeability. This study aimed to enhance the corneal permeability of SAHA by promoting its inclusion into a complex with hydroxypropyl-β-CD (HPβCD) for topical application. In phase-solubility studies, the solubility of SAHA with HPβCD and sulfobutyl ether-β-CD (SEβCD) was assessed at different temperatures, and complexation efficiencies (K) were calculated. The inclusion complexes (ICs) were prepared and characterized by differential scanning calorimetry (DSC), infrared spectrometry (IR), scanning electron microscopy (SEM), and X-ray diffraction (XRD) after freeze-drying. The phase-solubility study showed that the complexation efficiencies of SAHA were higher in HPβCD solutions (297.35 M, 115.28 M and 122.75 M) than in SEβCD solutions (169.75 M, 91.33 M and 96.49 M) at 4 °C, 25 °C and 37 °C. HPβCD was selected for SAHA-IC preparation, and characterization revealed IC formation. SAHA existed in an amorphous state in the ICs. The ex vivo corneal permeability of SAHA was also evaluated and found to be greater when formulated as an HPβCD solution than as a suspension. Irritation assays in rabbit eyes showed that the SAHA-IC solution was not irritating after topical application. The ocular pharmacokinetics of SAHA in New Zealand White rabbits were assessed following topical administration (0.2%), and a 0.2% SAHA suspension was used as the control. Compared to its formulation as a suspension, the formulation of SAHA as an HPβCD solution increased its corneal bioavailability by more than 3-fold and its conjunctival bioavailability by more than 2-fold. Thus, IC formation was effective at improving the ocular bioavailability of SAHA. This study provides an important alternative approach for developing liquid pharmaceutical formulations of SAHA for topical ocular applications.
Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Calorimetry, Differential Scanning; Cyclodextrins; Permeability; Pharmaceutical Preparations; Rabbits; Solubility; Vorinostat; X-Ray Diffraction
PubMed: 34838620
DOI: 10.1016/j.ejps.2021.106078