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John J Morrison - One of the best experts on this subject based on the ideXlab platform.
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Histone Deacetylase Inhibitors and a functional potent inhibitory effect on human uterine contractility.
American journal of obstetrics and gynecology, 2008Co-Authors: Audrey T Moynihan, Mark P Hehir, Aidan M Sharkey, Stephen C Robson, G Nicholas Europe-finner, John J MorrisonAbstract:This study was undertaken to investigate the effects of 3 Histone Deacetylase Inhibitors on human uterine contractility. Biopsy specimens of human myometrium were obtained at elective cesarean section (n = 18). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous, and oxytocin-induced contractions, were subjected to cumulative additions of 3 Histone Deacetylase Inhibitors: trichostatin A, suberic bishydroxamate (1 nmol/L-10 micromol/L) and valproic acid (100 nmol/L--1 mmol/L). Control experiments were run simultaneously. Integrals of contractile activity were measured by using the PowerLab hardware unit and Chart v3.6 software. Data were analyzed by using 1-way analysis of variance, followed by post hoc analysis. All 3 Histone Deacetylase inhibitor compounds exerted a potent and cumulative inhibitory effect on spontaneous (n = 18) and oxytocin-induced (n =18) contractility. The mean maximal inhibition values for the 3 compounds were as follows: trichostatin A, 46-54% (P < .05); valproic acid, 35-36% (P < .05); and suberic bishydroxamate, 53-65% (P < .05). The Histone Deacetylase Inhibitors trichostatin A, valproic acid, and suberic bishydroxamate exerted a potent inhibitory effect on human uterine contractions. This raises the possibility that this new class of compounds may have tocolytic potential, in addition to their current clinical indications. We speculate that this inhibitory effect may be linked, at least in part, to the ability of Histone Deacetylase Inhibitors to induce the expression of genes involved in maintaining myometrial quiescence via epigenetic mechanisms but may also potentially involve nonepigenetic pathways.
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Histone Deacetylase Inhibitors and a functional potent inhibitory effect on human uterine contractility
American Journal of Obstetrics and Gynecology, 2008Co-Authors: Audrey T Moynihan, Mark P Hehir, Aidan M Sharkey, Stephen C Robson, G Nicholas Europe-finner, John J MorrisonAbstract:Objective This study was undertaken to investigate the effects of 3 Histone Deacetylase Inhibitors on human uterine contractility. Study Design Biopsy specimens of human myometrium were obtained at elective cesarean section (n = 18). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous, and oxytocin-induced contractions, were subjected to cumulative additions of 3 Histone Deacetylase Inhibitors: trichostatin A, suberic bishydroxamate (1 nmol/L-10 μmol/L) and valproic acid (100 nmol/L - 1 mmol/L). Control experiments were run simultaneously. Integrals of contractile activity were measured by using the PowerLab hardware unit and Chart v3.6 software. Data were analyzed by using 1-way analysis of variance, followed by post hoc analysis. Results All 3 Histone Deacetylase inhibitor compounds exerted a potent and cumulative inhibitory effect on spontaneous (n = 18) and oxytocin-induced (n =18) contractility. The mean maximal inhibition values for the 3 compounds were as follows: trichostatin A, 46-54% ( P P P Conclusion The Histone Deacetylase Inhibitors trichostatin A, valproic acid, and suberic bishydroxamate exerted a potent inhibitory effect on human uterine contractions. This raises the possibility that this new class of compounds may have tocolytic potential, in addition to their current clinical indications. We speculate that this inhibitory effect may be linked, at least in part, to the ability of Histone Deacetylase Inhibitors to induce the expression of genes involved in maintaining myometrial quiescence via epigenetic mechanisms but may also potentially involve nonepigenetic pathways.
Audrey T Moynihan - One of the best experts on this subject based on the ideXlab platform.
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Histone Deacetylase Inhibitors and a functional potent inhibitory effect on human uterine contractility.
American journal of obstetrics and gynecology, 2008Co-Authors: Audrey T Moynihan, Mark P Hehir, Aidan M Sharkey, Stephen C Robson, G Nicholas Europe-finner, John J MorrisonAbstract:This study was undertaken to investigate the effects of 3 Histone Deacetylase Inhibitors on human uterine contractility. Biopsy specimens of human myometrium were obtained at elective cesarean section (n = 18). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous, and oxytocin-induced contractions, were subjected to cumulative additions of 3 Histone Deacetylase Inhibitors: trichostatin A, suberic bishydroxamate (1 nmol/L-10 micromol/L) and valproic acid (100 nmol/L--1 mmol/L). Control experiments were run simultaneously. Integrals of contractile activity were measured by using the PowerLab hardware unit and Chart v3.6 software. Data were analyzed by using 1-way analysis of variance, followed by post hoc analysis. All 3 Histone Deacetylase inhibitor compounds exerted a potent and cumulative inhibitory effect on spontaneous (n = 18) and oxytocin-induced (n =18) contractility. The mean maximal inhibition values for the 3 compounds were as follows: trichostatin A, 46-54% (P < .05); valproic acid, 35-36% (P < .05); and suberic bishydroxamate, 53-65% (P < .05). The Histone Deacetylase Inhibitors trichostatin A, valproic acid, and suberic bishydroxamate exerted a potent inhibitory effect on human uterine contractions. This raises the possibility that this new class of compounds may have tocolytic potential, in addition to their current clinical indications. We speculate that this inhibitory effect may be linked, at least in part, to the ability of Histone Deacetylase Inhibitors to induce the expression of genes involved in maintaining myometrial quiescence via epigenetic mechanisms but may also potentially involve nonepigenetic pathways.
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Histone Deacetylase Inhibitors and a functional potent inhibitory effect on human uterine contractility
American Journal of Obstetrics and Gynecology, 2008Co-Authors: Audrey T Moynihan, Mark P Hehir, Aidan M Sharkey, Stephen C Robson, G Nicholas Europe-finner, John J MorrisonAbstract:Objective This study was undertaken to investigate the effects of 3 Histone Deacetylase Inhibitors on human uterine contractility. Study Design Biopsy specimens of human myometrium were obtained at elective cesarean section (n = 18). Dissected myometrial strips suspended under isometric conditions, undergoing spontaneous, and oxytocin-induced contractions, were subjected to cumulative additions of 3 Histone Deacetylase Inhibitors: trichostatin A, suberic bishydroxamate (1 nmol/L-10 μmol/L) and valproic acid (100 nmol/L - 1 mmol/L). Control experiments were run simultaneously. Integrals of contractile activity were measured by using the PowerLab hardware unit and Chart v3.6 software. Data were analyzed by using 1-way analysis of variance, followed by post hoc analysis. Results All 3 Histone Deacetylase inhibitor compounds exerted a potent and cumulative inhibitory effect on spontaneous (n = 18) and oxytocin-induced (n =18) contractility. The mean maximal inhibition values for the 3 compounds were as follows: trichostatin A, 46-54% ( P P P Conclusion The Histone Deacetylase Inhibitors trichostatin A, valproic acid, and suberic bishydroxamate exerted a potent inhibitory effect on human uterine contractions. This raises the possibility that this new class of compounds may have tocolytic potential, in addition to their current clinical indications. We speculate that this inhibitory effect may be linked, at least in part, to the ability of Histone Deacetylase Inhibitors to induce the expression of genes involved in maintaining myometrial quiescence via epigenetic mechanisms but may also potentially involve nonepigenetic pathways.
Tom C. Karagiannis - One of the best experts on this subject based on the ideXlab platform.
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Controversies Surrounding the Potential Use of Histone Deacetylase Inhibitors for the Treatment of Asthma
ISRN Pulmonology, 2012Co-Authors: Simon G. Royce, Katherine Ververis, Tom C. KaragiannisAbstract:Management of asthma with long-acting
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Overview of the Classical Histone Deacetylase Enzymes and Histone Deacetylase Inhibitors
ISRN Cell Biology, 2012Co-Authors: Katherine Ververis, Tom C. KaragiannisAbstract:The important role of Histone Deacetylase enzymes in regulating gene expression, cellular proliferation, and survival has made them attractive targets for the development of Histone Deacetylase Inhibitors as anticancer drugs. Suberoylanilide hydroxamic acid (Vorinostat, Zolinza), a structural analogue of the prototypical Trichostatin A, was approved by the US Food and Drug Administration for the treatment of advanced cutaneous T-cell lymphoma in 2006. This was followed by approval of the cyclic peptide, depsipeptide (Romidepsin, Istodax) for the same disease in 2009. Currently numerous Histone Deacetylase Inhibitors are undergoing preclinical and clinical trials for the treatment of hematological and solid malignancies. Most of these studies are focused on combinations of Histone Deacetylase Inhibitors with other therapeutic modalities, particularly conventional chemotherapeutics and radiotherapy. The aim of this paper is to provide an overview of the classical Histone Deacetylase enzymes and Histone Deacetylase Inhibitors with an emphasis on potential combination therapies.
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Histone Deacetylase Inhibitors: Can We Consider Potent Anti-Neoplastic Agents for the Treatment of Asthma?
Annals of clinical and laboratory science, 2012Co-Authors: Simon G. Royce, Katherine Ververis, Tom C. KaragiannisAbstract:Histone Deacetylase Inhibitors have emerged as a new class of anti-cancer therapeutics due to their potent anti-proliferative and apoptotic effects in malignant cells. Accumulating evidence is indicating that Histone Deacetylase Inhibitors may also have potential clinical utility in non-oncological applications, including asthma. However, the potential of Histone Deacetylase Inhibitors in asthma remains controversial. For example, the mechanisms of action of the broad-spectrum Histone Deacetylase inhibitor, Trichostatin A, in animal models of allergic airways disease are conflicting. Further, there is evidence suggesting potential problems associated with Histone Deacetylase 2 inhibition and conventional glucocorticosteroid therapy. Similarly, disparate findings are emerging following modulation of the class III, sirtuin 1 enzyme. Indeed, it is becoming apparent that the mechanism of action may not be related to Histone Deacetylase inhibition activity per se. Further, there is only limited evidence that these compounds possess anti-inflammatory effects in models of asthma. In this review, we provide an overview of the biology of the metal-dependent and sirtuin Deacetylases in the context of asthma. The controversies surrounding the potential use of Histone Deacetylase Inhibitors in asthma are discussed and future directions involving the investigation of more specific analogues are explored.
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Potential non-oncological applications of Histone Deacetylase Inhibitors.
American journal of translational research, 2011Co-Authors: Katherine Ververis, Tom C. KaragiannisAbstract:Histone Deacetylase Inhibitors have emerged as a new class of anticancer therapeutic drugs. Their clinical utility in oncology stems from their intrinsic cytotoxic properties and combinatorial effects with other conventional cancer therapies. To date, the Histone Deacetylase Inhibitors suberoylanilide hydroxamic acid (Vorinostat, Zolinza®) and depsipeptide (Romidepsin, Istodax®) have been approved by the US Food and Drug Administration for the treatment of refractory cutaneous T-cell lymphoma. Further, there are currently over 100 clinical trials involving the use of Histone Deacetylase Inhibitors in a wide range of solid and hematological malignancies. The therapeutic potential of Histone Deacetylase Inhibitors has also been investigated for numerous other diseases. For example, the cytotoxic properties of Histone Deacetylase Inhibitors are currently being harnessed as a potential treatment for malaria, whereas the efficacy of these compounds for HIV relies on de-silencing latent virus. The anti-inflammatory properties of Histone Deacetylase Inhibitors are the predominant mechanisms for other diseases, such as hepatitis, systemic lupus erythematosus and a wide range of neurodegenerative conditions. Additionally, Histone Deacetylase Inhibitors have been shown to be efficacious in animal models of cardiac hypertrophy and asthma. Broad-spectrum Histone Deacetylase Inhibitors are clinically available and have been used almost exclusively in preclinical systems to date. However, it is emerging that class- or isoform-specific compounds, which are becoming more readily available, may be more efficacious particularly for non-oncological applications. The aim of this review is to provide an overview of the effects and clinical potential of Histone Deacetylase Inhibitors in various diseases. Apart from applications in oncology, the discussion is focused on the potential efficacy of Histone Deacetylase Inhibitors for the treatment of neurodegenerative diseases, cardiac hypertrophy and asthma.
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Histone Deacetylase Inhibitors augment doxorubicin-induced DNA damage in cardiomyocytes
Cellular and molecular life sciences : CMLS, 2011Co-Authors: Katherine Ververis, Annabelle L. Rodd, Michelle M. Tang, Assam El-osta, Tom C. KaragiannisAbstract:Histone Deacetylase Inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid (Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that Histone Deacetylase Inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies, involves the use of Histone Deacetylase Inhibitors with the anthracycline, doxorubicin. However, we previously identified that trichostatin A can potentiate doxorubicin-induced hypertrophy, the dose-limiting side-effect of the anthracycline, in cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the Histone Deacetylase Inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes. Using γH2AX as a molecular marker for the DNA lesions, we identified that all of the broad-spectrum Histone Deacetylase Inhibitors tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained nuclei that the Histone Deacetylase Inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight the importance of investigating potential side-effects, in relevant model systems, which may be associated with emerging combination therapies for cancer.
Simon J. Harrison - One of the best experts on this subject based on the ideXlab platform.
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clinical studies of Histone Deacetylase Inhibitors
Clinical Cancer Research, 2009Co-Authors: Miles H Prince, Mark Bishton, Simon J. HarrisonAbstract:Over the last 5 years, a plethora of Histone Deacetylase Inhibitors (HDACi) have been evaluated in clinical trials. These drugs have in common the ability to hyperacetylate both Histone and nonHistone targets, resulting in a variety of effects on cancer cells, their microenvironment, and immune responses. To date, responses with single agent HDACi have been predominantly observed in advanced hematologic malignancies including T-cell lymphoma, Hodgkin lymphoma, and myeloid malignancies. Therefore, in this review we focus upon hematologic malignancies. Generally HDACi are well tolerated with the most common acute toxicities being fatigue, gastrointestinal, and transient cytopenias. Of note, few patients have been treated for prolonged periods of time and little is known about long-term toxicities. The use of the biomarker of Histone hyperacetylation has been useful as a guide to target specificity, but generally does not predict for response and the search for more clinically relevant biomarkers must continue.
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The potential of Histone Deacetylase Inhibitors for the treatment of multiple myeloma.
Leukemia & lymphoma, 2008Co-Authors: H. Miles Prince, Mark Bishton, Simon J. HarrisonAbstract:Preclinical evidence supports the investigation of Histone Deacetylase Inhibitors for the treatment of myeloma. Results from early studies demonstrate clinical activity and further studies investigating combination strategies should be explored.
Susan E. Bates - One of the best experts on this subject based on the ideXlab platform.
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Histone Deacetylase Inhibitors and demethylating agents: clinical development of Histone Deacetylase Inhibitors for cancer therapy.
Cancer journal (Sudbury Mass.), 2007Co-Authors: Richard Piekarz, Dan L. Sackett, Susan E. BatesAbstract:The Histone Deacetylase Inhibitors are a new class of agents that are currently in various stages of clinical development. Clinical trials have demonstrated activity, urging further investigation. At the same time, it has been discovered that these agents have their own challenges. In this review, we discuss clinical data gathered to date, combination therapies designed to increase efficacy, and toxicities attributed to this new class of agents.
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Depletion of mutant p53 and cytotoxicity of Histone Deacetylase Inhibitors.
Cancer research, 2005Co-Authors: Mikhail V. Blagosklonny, Ganesh Kayastha, Susan E. Bates, Shana Y. Trostel, Zoya N. Demidenko, Lyubomir T. Vassilev, Larisa Y. Romanova, Tito FojoAbstract:Mutant p53 is a cancer-specific target for pharmacologic intervention. We show that Histone Deacetylase Inhibitors such as FR901228 and trichostatin A completely depleted mutant p53 in cancer cell lines. This depletion was preceded by induction of p53-regulated transcription. In cells with mutant p53 pretreated with Histone Deacetylase Inhibitors, DNA damage further enhanced the p53 trans-function. Furthermore, Histone Deacetylase Inhibitors were preferentially cytotoxic to cells with mutant p53 rather than to cells lacking wild-type p53. We suggest that, by either restoring or mimicking p53 trans-functions, Histone Deacetylase Inhibitors initiate degradation of mutant p53. Because mutant p53 is highly expressed, a sudden restoration of p53-like functions is highly cytotoxic to cells with mutant p53. In a broader perspective, this shows how selectivity may be achieved by targeting a non-cancer-specific target, such as Histone Deacetylases, in the presence of a cancer-specific alteration, such as mutant p53.
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t cell lymphoma as a model for the use of Histone Deacetylase Inhibitors in cancer therapy impact of depsipeptide on molecular markers therapeutic targets and mechanisms of resistance
Blood, 2004Co-Authors: Richard Piekarz, Ganesh Kayastha, Anousheh Sayah, Amina H Abdeldaim, Sonia Torrico, Zhirong Zhan, Robert W. Robey, Susan E. BatesAbstract:Depsipeptide (FK228) is a novel Histone Deacetylase inhibitor currently in clinical trials and the first to demonstrate clinical activity in patients. Responses have been observed in patients with T-cell lymphomas, despite prior treatment with multiple chemotherapeutic agents. To better understand the effects of Histone Deacetylase Inhibitors on T-cell lymphoma, the human T-cell lymphoma cell line HUT78 was tested for sensitivity and molecular response to depsipeptide. Treatment with depsipeptide, as well as other Histone Deacetylase Inhibitors, caused induction of Histone acetylation, induction of p21 expression, and substantial apoptosis without significant cell cycle arrest. Treatment with the caspase inhibitor z-VAD-fmk significantly inhibited depsipeptide-induced apoptosis, enabling detection of cell cycle arrest. Treatment with depsipeptide increased expression of the interleukin-2 (IL-2) receptor, and combination with the IL-2 toxin conjugate denileukin diftitox resulted in more than additive toxicity. Cells selected for resistance to depsipeptide overexpressed the multidrug resistance pump, P-glycoprotein (Pgp). However, cells selected for resistance to depsipeptide in the presence of a Pgp inhibitor had a Pgp-independent mechanism of resistance. These studies confirm the activity of depsipeptide in a T-cell lymphoma model and suggest a general sensitivity of T-cell lymphoma to Histone Deacetylase Inhibitors, an emerging new class of anticancer agents. (Blood. 2004;103:4636-4643)