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Journal of Medicinal Chemistry Jun 2023Histone deacetylases (HDACs) are enzymes pursued as drug targets in various cancers and several non-oncological conditions, such as inflammation and neurodegenerative... (Review)
Review
Histone deacetylases (HDACs) are enzymes pursued as drug targets in various cancers and several non-oncological conditions, such as inflammation and neurodegenerative disorders. In the past decade, HDAC inhibitors (HDACi) have emerged as relevant pharmaceuticals, with many efforts devoted to the development of new representatives. However, the growing safety concerns regarding the established hydroxamic acid-based HDAC inhibitors tend to drive current research more toward the design of inhibitors bearing alternative zinc-binding groups (ZBGs). This Perspective presents an overview of all non-hydroxamic acid ZBGs that have been incorporated into the clinically approved prototypical HDACi, suberoylanilide hydroxamic acid (vorinostat). This provides the unique opportunity to compare the inhibition potential and biological effects of different ZBGs in a direct way, as the compounds selected for this Perspective differ only in their ZBG. To that end, different strategies used to select a ZBG, its properties, activity, and liabilities are discussed.
Topics: Vorinostat; Histone Deacetylase Inhibitors; Hydroxamic Acids; Histone Deacetylases; Zinc
PubMed: 37276138
DOI: 10.1021/acs.jmedchem.3c00226 -
International Journal of Cancer Apr 2023The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common...
The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells. Among mitochondria-associated gene targets, we found that high expression of the mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2), was a strong predictor of poor neuroblastoma patient prognosis and contributed to a more malignant phenotype in pre-clinical models. Inhibiting this transporter with PENAO reduced cell viability in a panel of neuroblastoma cell lines in a TP53-status-dependant manner. We identified the histone deacetylase inhibitor, suberanilohydroxamic acid (SAHA), as the most effective drug in clinical use against mutant TP53 neuroblastoma cells. SAHA and PENAO synergistically reduced cell viability, and induced apoptosis, in neuroblastoma cells independent of TP53-status. The SAHA and PENAO drug combination significantly delayed tumour progression in pre-clinical neuroblastoma mouse models, suggesting that these clinically advanced inhibitors may be effective in treating the disease.
Topics: Animals; Mice; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Histone Deacetylase Inhibitors; Histones; Hydroxamic Acids; Mitochondria; Neuroblastoma; Vorinostat; Adenine Nucleotide Translocator 2
PubMed: 36346110
DOI: 10.1002/ijc.34349 -
ACS Omega Jan 20207-Ethyl-10-hydroxycamptothecin (SN38) and vorinostat (SAHA) are quite promising combination therapy agents applied to the clinical treatment of cancer. In this study, we...
7-Ethyl-10-hydroxycamptothecin (SN38) and vorinostat (SAHA) are quite promising combination therapy agents applied to the clinical treatment of cancer. In this study, we designed and synthesized a series of novel SN38-SAHA co-prodrugs, which were conjugated by four different amino acids including glycine, alanine, aminobutyric acid, and 6-aminocaproic acid. The hydrolytic reconversion rate to SN38 and SAHA critically depended on the carbon chain length, which were evaluated in PBS (pH 6.0/7.4) and plasma (human/mouse). With decreasing amino acid chain length, the hydrolytic reconversion rate increased gradually. The in vitro cytotoxicity test was evaluated by the sulforhodamine B (SRB) assay on the human lung adenocarcinoma cell line A549 and human colorectal cancer cell line HCT116. With the evaluation of stability and in vitro cytotoxicity, an appropriate linker was found, and the active drug can be released efficiently from compound , which exhibited strong antiproliferative activity in A549 and HCT-116 cell lines correspondingly. These results indicated that the well-designed co-prodrug and this kind of strategy can be a promising approach for anticancer therapy.
PubMed: 31956782
DOI: 10.1021/acsomega.9b02786 -
Journal of Separation Science Feb 2023While histone deacetylase inhibitors, such as vorinostat, demonstrate a significant effect against hematological cancers, their application for solid tumor treatment is...
Box-Behnken assisted development and validation of high-performance liquid chromatography method for the simultaneous determination of doxorubicin and vorinostat in polymeric nanoparticles.
While histone deacetylase inhibitors, such as vorinostat, demonstrate a significant effect against hematological cancers, their application for solid tumor treatment is limited. However, there is strong evidence that combinatorial administration of vorinostat and genotoxic agents (e.g., doxorubicin) enhances the antitumoral action of both drugs against tumors. We developed a high-performance liquid chromatography method for the simultaneous determination of doxorubicin and vorinostat in polymeric nanoparticles designed to provide the parenteral administration of both drugs and increase their safety profile. We performed separation on Nucleodur C-18 Gravity column with a mixture of 10 mM potassium dihydrogen phosphate buffer pH 3.9:ACN (90:10 v/v) as mobile phase at 240 nm. The method was linear within the concentration range of 4.2-52.0 μg/ml for both drugs with limits of detection and quantification of 3.5 and 10.7 μg/ml for doxorubicin and 2.5 and 7.7 μg/ml for vorinostat, respectively. The method was precise and accurate over the concentration range of analysis. Drug loading was 5.4% for doxorubicin and 0.8% for vorinostat. Degradation of doxorubicin after irradiation was less than 5%, while the amount of vorinostat decreased at 88% under the same conditions. Thus, the validated method could be adopted for routine simultaneous analysis of doxorubicin and vorinostat in polymeric nanoparticles.
Topics: Humans; Vorinostat; Chromatography, High Pressure Liquid; Doxorubicin; Histone Deacetylase Inhibitors; Neoplasms; Pharmaceutical Preparations; Nanoparticles
PubMed: 36427291
DOI: 10.1002/jssc.202200731 -
The AAPS Journal Oct 2021Ordinary differential equation (ODE)-based models of signal transduction pathways often contain parameters that are unidentifiable or unmeasurable by experimental data,...
Ordinary differential equation (ODE)-based models of signal transduction pathways often contain parameters that are unidentifiable or unmeasurable by experimental data, and calibrating such models to data remains challenging. Here, two efficient parameter estimation methods, cluster Gauss-Newton (CGN) and CellNOpt (CNO), were applied to fit a signaling network model of U266 multiple myeloma cells to the activity dynamics of key proteins in response to vorinostat and/or bortezomib. A logic-based network model was constructed and transformed to 17 ODEs with 79 parameters estimated within broad ranges of biologically plausible values. The top 10% best-fit parameters by both methods had high uncertainties with CV > 50% for the majority of parameters. The root mean square and prediction errors were comparable without statistically significant differences between the two methods. Despite uncertain parameter estimation, protein dynamics after the sequential combination of bortezomib and vorinostat was predicted with reasonable accuracy and precision. Global sensitivity analyses of partial rank correlation coefficients and Sobol sensitivity demonstrated that apoptosis induction was most sensitive to parameters governing the activity of the proteasome-JNK-caspase-8 axis. Simulations revealed that the greatest magnitude of pharmacodynamic drug interactions between bortezomib and vorinostat occurred at caspase-9, AKT, and Bcl-2. Two sequential combinations were explored in silico, and the outcome matched qualitatively with an empirical evaluation of the pharmacodynamic interaction based on cell viability. Overall, the CGN and CNO algorithms performed similarly for this ODE-based network model calibration, and the calibrated model provided meaningful insights into cellular signaling mechanisms in response to pharmacological perturbations.
Topics: Algorithms; Antineoplastic Agents; Bortezomib; Cell Line, Tumor; Computer Simulation; Drug Interactions; Humans; Models, Theoretical; Multiple Myeloma; Signal Transduction; Vorinostat
PubMed: 34622346
DOI: 10.1208/s12248-021-00640-7 -
Medical Oncology (Northwood, London,... Oct 2022The process of cancer initiation and development is regulated via the transcriptional expression of cells going under genomic and epigenetic changes. Targeting...
The process of cancer initiation and development is regulated via the transcriptional expression of cells going under genomic and epigenetic changes. Targeting epigenetic "readers", i.e., bromodomains (BRD) and post-translational modifications of nucleosomal histone proteins regulate gene expression in both cancerous and healthy cells. In this study, the new epigenetic agent BRD inhibitor PLX51107 and histone deacetylase (HDAC) inhibitor SAHA' s (Vorinostat) single/combined applications' reflections were analyzed in case of cell proliferation, cytotoxicity, apoptosis, cell cycle arrest, and finally target gene expression regulation upon both AML and healthy B-lymphocyte cells; HL60 and NCIBL2171, respectively; in vitro. Since mono treatments of either Vorinostat or Plx51107 regulated cellular responses such as growth, proliferation, apoptosis, and cell cycle arrest of tumor cells; their combination treatments exerted accelerated results. We detected that combined treatment of Plx51107 and Vorinostat strengthened effects detected upon leukemic cells for gaining more sensitization to the agents, decreasing cell proliferation, dramatically inducing apoptosis, and cell cycle arrest; thus regulating target gene expressions. We have shown for the first time that the newly analyzed BRD inhibitor Plx51107 could be a promising therapeutic approach for hematological malignancies and its mono or combined usage might support a rapid transition to clinical trials.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Hydroxamic Acids; Leukemia, Myeloid, Acute; Oxazoles; Pyridines; Pyrroles; Vorinostat
PubMed: 36224430
DOI: 10.1007/s12032-022-01858-x -
Mediterranean Journal of Hematology and... 2022Cutaneous T-cell lymphomas are a heterogeneous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary... (Review)
Review
Cutaneous T-cell lymphomas are a heterogeneous group of T-cell neoplasms involving the skin, the majority of which may be classified as Mycosis Fungoides (MF) or Sézary Syndrome (SS). Mycosis fungoides (MF) is usually associated with an indolent clinical course and intermittent, stable, or slow progression of the lesions. Extracutaneous involvement (lymph nodes, blood, or less commonly other organs) or large cell transformation (LCT) may be seen in advanced-stage disease. Sezary syndrome (SS) is a rare leukemic subtype of CTCL characterized by significant blood involvement, erythroderma, and often lymphadenopathy. Although the early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary to treat advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as vorinostat, brentuximab vedotin, and mogamulizumab. This review aims to discuss the diagnosis and management of advanced-stages MF and SS.
PubMed: 35444765
DOI: 10.4084/MJHID.2022.029 -
Parasitology International Oct 2023Babesia gibsoni is mainly transmitted by hard ticks of the genus Rhipicephalus (R. sanguineus) and Haemaphysalis (H. longicornis), and causes canine babesiosis. Clinical...
In vitro screening of compounds from the Food and Drug Administration-approved library identifies anti-Babesia gibsoni activity of idarubicin hydrochloride and vorinostat.
Babesia gibsoni is mainly transmitted by hard ticks of the genus Rhipicephalus (R. sanguineus) and Haemaphysalis (H. longicornis), and causes canine babesiosis. Clinical manifestations of B. gibsoni infection include fever, hemoglobinemia, hemoglobinuria, and progressive anemia. Traditional antibabesial therapy, such as imidocarb dipropionate or diminazene aceturate, can only alleviate severe clinical manifestations and cannot eliminate parasites in the host. Food and Drug Administration (FDA)-approved drugs are a solid starting point for researching novel therapy strategies for canine babesiosis. In this work, we screened 640 FDA-approved drugs against the growth of B. gibsoni in vitro. Among them, 13 compounds (at 10 μM) exhibited high growth inhibition (>60%), and two compounds, namely idarubicin hydrochloride (idamycin) and vorinostat, were chosen for further investigation. The half-maximal inhibitory concentration (IC) values of idamycin and vorinostat were determined to be 0.044 ± 0.008 μM and 0.591 ± 0.107 μM, respectively. Viability results indicated that a concentration of 4 × IC of vorinostat prevented the regrowth of treated B. gibsoni, whereas parasites treated with 4 × IC concentration of idamycin remained viable. The B. gibsoni parasites treated with vorinostat exhibited degeneration within erythrocytes and merozoites, in contrast to the oval or signet-ring shape of normal B. gibsoni parasites. In conclusion, FDA-approved drugs offer a valuable platform for drug repositioning in antibabesiosis research. Particularly, vorinostat demonstrated promising inhibitory effects against B. gibsoni in vitro, and further studies on vorinostat are necessary to elucidate its mechanism as a novel treatment in infected animal models.
Topics: United States; Animals; Dogs; Babesia; Babesiosis; Vorinostat; Idarubicin; United States Food and Drug Administration; Ixodidae; Dog Diseases
PubMed: 37380124
DOI: 10.1016/j.parint.2023.102774 -
Future Medicinal Chemistry Jul 2021
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Neoplasms; Vorinostat
PubMed: 33960205
DOI: 10.4155/fmc-2021-0102 -
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