The Emerging Role of Histone Deacetylase Inhibitors in the Treatment of Lymphoma
Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey in 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).
Multiple endocrine neoplasia type 1
J. K. Cowell in Molecular Genetics of Cancer, 2003
Using yeast two-hybrid systems, an interacting protein of menin has been isolated which turns out to be the API transcription factor JUND (Agarwal et al., 1999). The API transcription factors have basic leucine zipper (bZip) domains that pair to bind DNA as a Y-shaped heterodimer. Menin has been found to specifically bind to JUND via its N-terminal, but not to the other members of JUN or FOS. Menin causes repression on JUND-activated transcription and one recent study has shown that this repression is released by the histone deacetylase inhibitor trichostatin A, suggesting that the repression is dependent on histone deacetylation (Gobl et al., 1999). Some, but not all, MEN1 mutations disrupt its binding to JUND causing an increase in JUND-activated transcription. Based on the binding effects demonstrated by MEN1 mutations from different locations, three binding domains have been identified: amino acids 1–40, 139–242 and 323–428 (Figure 1)and there are a number of disease-causing mutations that are located outside the binding domains. The identification of other interacting proteins, which may constitute parts of the menin-JUND complex or separate functional entities, may further elucidate the molecular mechanisms involved in MEN1 tumorigenesis.
Medical Therapies
Nazar N. Amso, Saikat Banerjee in Endometriosis, 2022
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).
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].
How do we improve histone deacetylase inhibitor drug discovery?
Published in Expert Opinion on Drug Discovery, 2020
The dynamic status of histone acetylation is under the control of histone deacetylases (HDACs) and histone acetyltransferases (HATs), which play an important role in the regulation of gene expression. While HATs mediate the acetylation of lysine residue associated with gene transcription, HDACs have the opposite effect, and deacetylation leads to a more condensed chromatin structure; this, in turn, leads to transcriptional repression of the gene [1]. Histone deacetylases are often dysregulated and have been recognized as a crucial factor in numerous diseases, including cancer, neurodegenerative and inflammatory diseases [2]. High expression of HDAC8 is correlated with poor survival and advanced disease in neuroblastoma [3]. While high expression levels of HDAC1, 2, and 3 have been shown to be associated with poor patient outcomes in gastric and ovarian cancers [4,5], HDACis have pleiotropic cellular effects including the arrest of cell growth, cell cycle progression, and the induction of apoptosis [6]. Numerous HDACis are nowadays at various stages of clinical trial development for the treatment of cancers. The natural hydroxamate Trichostatin A has served as a lead compound, for the development of the first approved HDACi vorinostat (SAHA). To date, five HDACis have been approved for the treatment of cutaneous T-cell lymphoma. These drugs can be classified into three chemical families: the class of hydroxamic acids such as vorinostat, panobinostat, and belinostat; the class of cyclic peptides such as romidepsin; and the class of o-amino anilides such as chidamide.
Related Knowledge Centers
- DNA
- Enzyme
- Enzyme Inhibitor
- Eukaryote
- Gene Expression
- Histone
- Histone Deacetylase
- Sirtuin
- Cell Cycle
- Transcription Factor