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The Oncologist Oct 2020The cholangiocarcinoma community has truly lost a young, talented, bright star, Dr. Supriya Kumar “Shoop” Saha. Despite his passing, he continues to inspire the...
The cholangiocarcinoma community has truly lost a young, talented, bright star, Dr. Supriya Kumar “Shoop” Saha. Despite his passing, he continues to inspire the search for a cure.
Topics: Apoptosis; Cell Line, Tumor; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Vorinostat
PubMed: 32835448
DOI: 10.1634/theoncologist.2020-0710 -
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 Parameterization of drug and system-specific processes was based on published and unpublished in silico, in vivo, and in vitro data.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 -
Biochemical Pharmacology Aug 2020The combination of the multi-kinase and chaperone inhibitor sorafenib and the histone deacetylase inhibitor vorinostat in pancreatic cancer patients has proven to be a... (Clinical Trial)
Clinical Trial
The combination of the multi-kinase and chaperone inhibitor sorafenib and the histone deacetylase inhibitor vorinostat in pancreatic cancer patients has proven to be a safe and efficacious modality (NCT02349867). We determined the evolutionary mechanisms by with pancreatic tumors become resistant to [sorafenib + vorinostat] and developed a new three-drug therapy to circumvent the resistant phenotype. Pancreatic tumors previously exposed to [sorafenib + vorinostat] evolved to activate the receptors ERBB1, ERBB2, ERBB3, c-MET and the intracellular kinase AKT. The irreversible ERBB receptor family and MAP4K inhibitor neratinib significantly enhanced the anti-tumor efficacy of [sorafenib + vorinostat]. We then determined the mechanisms by which neratinib enhanced the efficacy of [sorafenib + vorinostat]. Compared to [sorafenib + vorinostat] or to neratinib alone, the three-drug combination further enhanced the phosphorylation of eIF2α and NFκB and the expression of Beclin1, ATG5 and CD95; and suppressed the levels of β-catenin. Knock down of Beclin1, ATG5, CD95, eIF2 α or NFκB suppressed cell killing whereas knock down of β-catenin enhanced killing. The drugs interacted to increase autophagosome formation; and autophagy and cell killing were suppressed by expression of activated mTOR. A portion of the killing mechanism required CD95 signaling and knock down of NFκB prevented the drugs from increasing CD95 expression. We conclude that neratinib, by down-regulation of evolutionary activated growth factor receptors, may represent a novel follow-on clinical concept after the completion of NCT02349867.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Cell Line, Tumor; Cell Survival; Female; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Quinolines; Sorafenib; Vorinostat
PubMed: 32504550
DOI: 10.1016/j.bcp.2020.114067 -
Biomolecules Jun 2023Abnormal expression of histone deacetylases (HDACs) is reported to be associated with angiogenesis, metastasis and chemotherapy resistance regarding cancer in a wide...
Abnormal expression of histone deacetylases (HDACs) is reported to be associated with angiogenesis, metastasis and chemotherapy resistance regarding cancer in a wide range of previous studies. Suberoylanilide hydroxamic acid (SAHA) is well known to function as a pan-inhibitor for HDACs and recognized as one of the therapeutic drug candidates to epigenetically coordinate cancer cell fate regulation on a genomic scale. Here, we established a Real-Time Search (RTS)-assisted mass spectrometric platform for system-wide quantification of translated products encoded by non-canonical short open reading frames (ORFs) as well as already annotated protein coding sequences (CDSs) on the human transciptome and applied this methodology to quantitative proteomic analyses of suberoylanilide hydroxamic acid (SAHA)-treated human HeLa cells to evaluate proteome-wide regulation in response to drug perturbation. Very intriguingly, our RTS-based in-depth proteomic analysis enabled us to identify approximately 5000 novel peptides from the ribosome profiling-based short ORFs encoded in the diversified regions on presumed 'non-coding' nucleotide sequences of mRNAs as well as lncRNAs and nonsense mediated decay (NMD) transcripts. Furthermore, TMT-based multiplex large-scale quantification of the whole proteome changes upon differential SAHA treatment unveiled dose-dependent selective translational regulation of a limited fraction of the non-canonical short ORFs in addition to key cell cycle/proliferation-related molecules such as UBE2C, CENPF and PRC1. Our study provided the first system-wide landscape of drug-perturbed translational modulation on both canonical and non-canonical proteome dynamics in human cancer cells.
Topics: Humans; Vorinostat; Proteomics; Open Reading Frames; HeLa Cells; Proteome; Histone Deacetylases; Hydroxamic Acids; Histone Deacetylase Inhibitors
PubMed: 37371559
DOI: 10.3390/biom13060979 -
PloS One 2021Endoplasmic reticulum (ER) stress is associated with acute kidney injury (AKI) caused by various mechanisms, including antibiotics, non-steroidal anti-inflammatory...
Endoplasmic reticulum (ER) stress is associated with acute kidney injury (AKI) caused by various mechanisms, including antibiotics, non-steroidal anti-inflammatory drugs, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic that induces ER stress and is a commonly used model of AKI. 4-phenylbutyrate (4-PBA) is a chemical chaperone and histone deacetylase (HDAC) inhibitor and has been shown to protect the kidney from ER stress, apoptosis, and structural damage in a tunicamycin model of AKI. The renal protection provided by 4-PBA is attributed to its ability to prevent misfolded protein aggregation and inhibit ER stress; however, the HDAC inhibitor effects of 4-PBA have not been examined in the TM-induced model of AKI. As such, the main objective of this study was to determine if histone hyperacetylation provides any protective effects against TM-mediated AKI. The FDA-approved HDAC inhibitor vorinostat was used, as it has no ER stress inhibitory effects and therefore the histone hyperacetylation properties alone could be investigated. In vitro work demonstrated that vorinostat inhibited histone deacetylation in cultured proximal tubular cells but did not prevent ER stress or protein aggregation induced by TM. Vorinostat induced a significant increase in cell death, and exacerbated TM-mediated total cell death and apoptotic cell death. Wild type male mice were treated with TM (0.5 mg/kg, intraperitoneal injection), with or without vorinostat (50 mg/kg/day) or 4-PBA (1 g/kg/day). Mice treated with 4-PBA or vorinostat exhibited similar levels of histone hyperacetylation. Expression of the pro-apoptotic protein CHOP was induced with TM, and not inhibited by vorinostat. Further, vorinostat did not prevent any renal damage or decline in renal function caused by tunicamycin. These data suggest that the protective mechanisms found by 4-PBA are primarily due to its molecular chaperone properties, and the HDAC inhibitors used did not provide any protection against renal injury caused by ER stress.
Topics: Acute Kidney Injury; Animals; Cell Line; Disease Models, Animal; Endoplasmic Reticulum Stress; Histone Deacetylase Inhibitors; Male; Mice; Protein Aggregation, Pathological; Tunicamycin; Vorinostat
PubMed: 34847196
DOI: 10.1371/journal.pone.0260519 -
International Journal of Molecular... Oct 2021Histone deacetylase inhibitors (HDACis) are one of the therapeutic options for cutaneous T-cell lymphoma (CTCL), but they have limited effects. We previously...
Histone deacetylase inhibitors (HDACis) are one of the therapeutic options for cutaneous T-cell lymphoma (CTCL), but they have limited effects. We previously demonstrated that HSP72 overexpression is associated with chemoresistance to HDACis in lymphoma cells. The purpose of this study was to investigate whether the functional depletion of HSP72 enhances the effect of the HDACi vorinostat. First, we established a stable HSP72-knockdown CTCL cell line and confirmed the influence of HSP72 reduction on the antitumor effects of vorinostat. Next, we studied the effect of quercetin, an inhibitor of HSP72, on the antineoplastic effects of vorinostat. In five CTCL cell lines examined, HSP72 expression was highest in Hut78 cells, and HSP72 knockdown enhanced vorinostat-induced apoptosis in these cells. Low-dose quercetin reduced HSP72 expression, increased HDAC activity, and enhanced vorinostat-induced suppression of Hut78 cell proliferation. A single low dose of quercetin induced G2 arrest and only slightly increased the sub-G1 cell fraction. Quercetin also significantly enhanced vorinostat-induced apoptosis, caspase-3, caspase-8, and caspase-9 activity, and the loss of mitochondrial membrane potential. HSP72 knockdown enhanced vorinostat-induced apoptosis in an HSP72-overexpressing CTCL cell line, and thus, quercetin may be a suitable candidate for combination therapy with vorinostat in clinical settings.
Topics: Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HSP72 Heat-Shock Proteins; Histone Deacetylases; Humans; Lymphoma, T-Cell, Cutaneous; Quercetin; RNA, Small Interfering; Skin Neoplasms; Vorinostat
PubMed: 34681913
DOI: 10.3390/ijms222011258 -
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 -
Scientific Reports Apr 2024Triple-negative breast cancer (TNBC) is a metastatic disease and a formidable treatment challenge as it does not respond to existing therapies. Epigenetic regulators...
Triple-negative breast cancer (TNBC) is a metastatic disease and a formidable treatment challenge as it does not respond to existing therapies. Epigenetic regulators play a crucial role in the progression and metastasis by modulating the expression of anti-apoptotic, pro-apoptotic markers and related miRNAs in TNBC cells. We have investigated the anti-TNBC potential of dietary flavonoid 'Apigenin' and its combination with Vorinostat on MDA-MB-231 cells. At Apigenin generated ROS, inhibited cell migration, arrested the cell cycle at subG0/G1 phases, and induced apoptotic-mediated cell death. Apigenin reduced the expression of the class-I HDACs at the transcriptomic and proteomic levels. In the immunoblotting study, Apigenin has upregulated pro-apoptotic markers and downregulated anti-apoptotic proteins. Apigenin inhibited the enzymatic activity of HDAC/DNMT and increased HAT activity. Apigenin has manifested its effect on miRNA expression by upregulating the tumor-suppressor miR-200b and downregulation oncomiR-21. Combination study reduced the growth of TNBC cells synergistically by modulating the expression of epigenetic and apoptotic regulators. Molecular docking and MD simulations explored the mechanism of catalytic inhibition of HDAC1 and HDAC3 and supported the in-vitro studies. The overall studies demonstrated an anti-TNBC potential of Apigenin and may help to design an effective strategy to treat metastatic phenotype of TNBC.
Topics: Apigenin; Humans; MicroRNAs; Triple Negative Breast Neoplasms; Apoptosis; Vorinostat; Epigenesis, Genetic; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Female; Cell Movement; Molecular Docking Simulation; Cell Proliferation
PubMed: 38664447
DOI: 10.1038/s41598-024-60395-x -
Journal of Advanced Research Sep 2023Hyperactivated histone deacetylases (HDACs) act as epigenetic repressors on gene transcription and are frequently observed in human hepatocellular carcinoma (HCC)....
Thioredoxin-interacting protein-activated intracellular potassium deprivation mediates the anti-tumour effect of a novel histone acetylation inhibitor HL23, a fangchinoline derivative, in human hepatocellular carcinoma.
INTRODUCTION
Hyperactivated histone deacetylases (HDACs) act as epigenetic repressors on gene transcription and are frequently observed in human hepatocellular carcinoma (HCC). Although multiple pharmacological HDAC inhibitors (HDACis) have been developed, none is available in human HCC.
OBJECTIVES
To investigate the pharmacological effects of a fangchinoline derivative HL23, as a novel HDACi and its molecular mechanisms through TXNIP-mediated potassium deprivation in HCC.
METHODS
Both in vitro assays and orthotopic HCC mouse models were used to investigate the effects of HL23 in this study. The inhibitory activity of HL23 on HDACs was evaluated by in silico studies and cellular assays. Chromatin immunoprecipitation (ChIP) was conducted to confirm the regulation of HL23 on acetylation mark at TXNIP promoter. Genome-wide transcriptome analysis together with bioinformatic analysis were conducted to identify the regulatory mechanisms of HL23. The clinical significance of TXNIP and HDACs was evaluated by analysing publicly available database.
RESULTS
HL23 exerted compatible HDACs inhibition potency as Vorinostat (SAHA) while had superior anti-HCC effects than SAHA and sorafenib. Both in vitro and in vivo studies showed HL23 significantly suppressed HCC progression and metastasis. HL23 significantly upregulated TXNIP expression via regulating acetylation mark (H3K9ac) at TXNIP promoter. TXNIP was responsible for anti-HCC activity of HL23 through mediating potassium channel activity. HDAC1 was predicted to be the target of HL23 and HDAC1TXNIP could jointly predict promising survival outcome of patients with HCC. Combination treatment with HL23 and sorafenib could significantly enhance sorafenib efficacy.
CONCLUSION
Our study identified HL23 as a novel HDACi through enhancing acetylation at TXNIP promoter to trigger TXNIP-dependent potassium deprivation and enhance sorafenib efficacy in HCC treatment.
Topics: Mice; Animals; Humans; Carcinoma, Hepatocellular; Sorafenib; Histones; Liver Neoplasms; Acetylation; Vorinostat; Histone Deacetylases; Thioredoxins
PubMed: 36351536
DOI: 10.1016/j.jare.2022.10.017 -
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