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Medical Therapies
Published in Nazar N. Amso, Saikat Banerjee, Endometriosis, 2022
Simone Ferrero, Fabio Barra, Giulio Evangelisti, Matteo Tantari
Previous studies have investigated the epigenetic components of endometriosis, reporting that variations in epigenetic patterns of specific genes may have a role in abnormal, hormonal, immune and inflammatory states that characterized this benign chronic disease (183,184). Histone deacetylases may also have a role in controlling the expression of steroid hormone-related genes (185). Inhibitors of histone deacetylases, such as trichostatin A and valproic acid, have been preliminarily investigated in endometriosis. In a preclinical study, trichostatin A exerted antiproliferative activity against endometrial stromal cells with more potent and longer-lasting effect than SPRMs and N-acetylcysteine. In particular, trichostatin A induced block of the cell cycle by inhibiting the action of COX-2 (186,187). In another preclinical study on mice, trichostatin A caused a significant decrease in endometriotic implant size (188). Valproic acid given to rats was effective in decreasing the size of endometriotic implants; moreover, it was well tolerated (189). Interestingly, a pilot study demonstrated that the administration of valproic acid in 12 women with certain diagnosis of adenomyosis, who complained of dysmenorrhea and had enlarged uterus, caused complete resolution of symptoms as well as an average reduction in uterine size by 26% after six months of therapy (190). Currently, no clinical trials on valproic acid for the treatment of women with endometriosis have been published (191).
The Emerging Role of Histone Deacetylase Inhibitors in the Treatment of Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
One natural product, trichostatin A (TSA), is among one of the most potent HDAC inhibitors but cannot be studied in the clinic secondary to its significant toxicity (20). Treatment of malignant lymphoid cells with TSA induces accumulation of cells in G0/G1 or G2/M phases, and causes a concomitant decrease of cells in S phase, eventually leading to apoptosis (21). TSA has served as a structural model for how hydroxamates are thought to exert their activity. Through crystallographic analysis, it has been shown that TSA contains three components: a hydroxamic acid residue that binds to the Zn ion of the HDAC, a hydrophobic spacer that helps in spanning the entire active center, and a hydrophobic cap that covers the active center therefore disabling the HDAC enzymatic activity. It was an understanding of these important structure activity relationships that eventually led to the development of the hydroxamic acids, of which suberolyanilide hydroxamic acid (SAHA, vorinostat) has become the best known representative. Treatment of normal and malignant cells with HDAC inhibitors leads to accumulation of acetylated histones H2A, H2B, H3, and H4 (22,23). Fortunately however, neoplastic cells seem to be much more sensitive to the growth inhibitory and apoptotic effects of these agents compared with normal cells (24).
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Trichostatin A (TSA) was one of the first HDAC inhibitors to be identified (Figure 5.111). Although it has been used extensively in laboratory experiments to demonstrate proof of concept of HDAC inhibition, it has not yet been approved for clinical use. Although trichostatin A was originally identified as an antifungal agent, it was later shown to selectively inhibit HDACs 1, 3, 4, 6, and 10 with IC50 values of ~20 nM. Data from in vitro experiments suggest that TSA promotes the expression of apoptosis-related genes, leading to a lower survival of cancer cells. Other suggestions are that it may induce cell differentiation, thus acting to “mature” some of the de-differentiated cells found in tumors. Although TSA is not approved for clinical use, three HDAC inhibitors, romidepsin (IstodaxTM), vorinostat (ZolinzaTM), and panobinostat (FarydakTM) have been approved by the FDA, and panobinostat is recommended by NICE for use in the UK (Figure 5.111). Structures of the HDAC inhibitors trichostatin A (TSA), romidepsin (IstodaxTM), vorinostat (ZolinzaTM), and panobinostat (FarydakTM).
Telomerase: a good target in hepatocellular carcinoma? An overview of relevant preclinical data
Published in Expert Opinion on Therapeutic Targets, 2022
Maria Lina Tornesello, Anna Lucia Tornesello, Noemy Starita, Andrea Cerasuolo, Francesco Izzo, Luigi Buonaguro, Franco Maria Buonaguro
The histone deacetylases inhibitors (HDAC) Trichostatin A has shown to induce high levels of TERT transcripts in the hepatocytes by enhancing the recruitment of Myc/Max heterodimer on TERT promoter [137]. Therefore, Trichostatin A and perhaps also other HDAC inhibitors may have the potential to be used as chemopreventive treatments in cirrhosis [138–140]. Trichostatin A determines the acetylation of CCAAT/enhancer binding protein α (C/EBP-α) and the increase in protein levels through the inhibition of its ubiquitination thus inhibiting hepatic stellate cells activation [141]. Trichostatin A administration has been observed to induce the reversion of the fibrotic process in a mouse model of liver fibrosis caused by carbon tetrachloride intoxication and to improve liver function. Such results demonstrated that the use of Trichostatin A may reduce hepatic fibrosis by suppressing hepatic stem cell activation, which is a key process in the initiation and progression of hepatic fibrosis [141].
Polyglutamine spinocerebellar ataxias: emerging therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2020
Andreia Neves-Carvalho, Sara Duarte-Silva, Andreia Teixeira-Castro, Patrícia Maciel
In addition to targeting the abnormal PPIs directly, therapeutic agents may also be directed at their downstream consequences – as is the case for histone deacetylase (HDAC) inhibitors, used to surpass the transcriptional repression seen in some models of polyQ SCAs. Promising results were obtained using valproic acid, sodium valproate or a mixture of both, sodium butyrate and trichostatin A in some cellular and animal models of SCA3 (Reviewed in [180]), and with sodium valproate in a clinical trial in SCA3 patients, but not confirmed in other models of the same disease. Interestingly, valproic acid was proposed to exert its effects through CREB-dependent transcriptional activation [162,163,171,180–182], CREB being a well-known ataxin-3 interactor. Trichostatin A was also shown to have beneficial effects in SCA7 [182].
HDAC inhibitors: a 2013–2017 patent survey
Published in Expert Opinion on Therapeutic Patents, 2018
Micaela Faria Freitas, Muriel Cuendet, Philippe Bertrand
The typical structure of HDACis contains a zinc-binding group (ZBG) (Figure 1(a)) connected to a so-called ‘cap’ group, mainly aromatic, by a linker. ZBGs include hydroxamic acids (i.e. vorinostat 1, Figure 1(b)), which are the most potent compounds, 2-aminobenzamides (i.e. entinostat 2), which are usually selective for class I HDACs, the thiols or their disulphide prodrug like romidepsin 3, and some other groups, such as the weak inhibitors carboxylic acids (i.e. valproic acid 4) and the trifluoromethyl derivatives (i.e. TMP25 5). Two compounds with other ZBGs should still be mentioned. It is trichostatin A 6, a natural compound highly potent but toxic that has inspired several analogs, and tubastatin 7, a commonly used HDAC6 selective inhibitor.