Histone Deacetylase Inhibitors from Marine Invertebrates

ChemInform, 2004

Three new cyclostellettamines, cyclostellettamine G (1), dehydrocyclostellettamines D (2), and E (3), were isolated together with the known cyclostellettamine A (4) from a marine sponge of the genus Xestospongia as histone deacetylase inhibitors. Their structures were determined by spectral and chemical methods. They inhibit histone deacetylase derived from K562 human leukemia cells with IC 50 values ranging from 17 to 80 lM.

Bioorganic & Medicinal Chemistry Letters, 2004

Three new cyclostellettamines, cyclostellettamine G (1), dehydrocyclostellettamines D (2), and E (3), were isolated together with the known cyclostellettamine A (4) from a marine sponge of the genus Xestospongia as histone deacetylase inhibitors. Their structures were determined by spectral and chemical methods. They inhibit histone deacetylase derived from K562 human leukemia cells with IC 50 values ranging from 17 to 80 lM.

Journal of Pharmacology and Experimental Therapeutics, 2010

Histone deacetylases (HDACs) are validated targets for anticancer therapy as attested by the approval of suberoylanilide hydroxamic acid (SAHA) and romidepsin (FK228) for treating cutaneous T cell lymphoma. We recently described the bioassay-guided isolation, structure determination, synthesis, and target identification of largazole, a marine-derived antiproliferative natural product that is a prodrug that releases a potent HDAC inhibitor, largazole thiol. Here, we characterize the anticancer activity of largazole by using in vitro and in vivo cancer models. Screening against the National Cancer Institute's 60 cell lines revealed that largazole is particularly active against several colon cancer cell types. Consequently, we tested largazole, along with several synthetic analogs, for HDAC inhibition in human HCT116 colon cancer cells. Enzyme inhibition strongly correlated with the growth inhibitory effects, and differential activity of largazole analogs was rationalized by mo-lecular docking to an HDAC1 homology model. Comparative genomewide transcript profiling revealed a close overlap of genes that are regulated by largazole, FK228, and SAHA. Several of these genes can be related to largazole's ability to induce cell cycle arrest and apoptosis. Stability studies suggested reasonable bioavailability of the active species, largazole thiol. We established that largazole inhibits HDACs in tumor tissue in vivo by using a human HCT116 xenograft mouse model. Largazole strongly stimulated histone hyperacetylation in the tumor, showed efficacy in inhibiting tumor growth, and induced apoptosis in the tumor. This effect probably is mediated by the modulation of levels of cell cycle regulators, antagonism of the AKT pathway through insulin receptor substrate 1 down-regulation, and reduction of epidermal growth factor receptor levels.

Genes & Nutrition, 2012

Protein acetylation status results from a balance between histone acetyltransferase and histone deacetylase (HDAC) activities. Alteration of this balance leads to a disruption of cellular integrity and participates in the development of numerous diseases, including cancer. Therefore, modulation of these activities appears to be a promising approach for anticancer therapy. Histone deacetylase inhibitors (HDACi) are epigenetically active drugs that induce the hyperacetylation of lysine residues within histone and non-histone proteins, thus affecting gene expression and cellular processes such as proteinprotein interactions, protein stability, DNA binding and protein sub-cellular localization. Therefore, HDACi are promising anti-tumor agents as they may affect the cell cycle, inhibit proliferation, stimulate differentiation and induce apoptotic cell death. Over the last 30 years, numerous synthetic and natural products, including a broad range of dietary compounds, have been identified as HDACi. This review focuses on molecules from natural origins modulating HDAC activities and presenting promising anticancer activities.

Angewandte Chemie International Edition, 2006

Current protein & peptide science, 2018

Acetylation and deactylation of histones are important determinants of gene expression. Histone deacetylases (HDACs) remove acetyl groups from histones leading to suppression and regulation of epigenetic gene expression. Current studies have demonstrated that HDAC-inhibitors (HDACIs) inducing histone hyperacetylation are promising novel agents in cancer treatment. HDACIs have been shown to have significant anticancer effects with negligible toxicity in the preclinical studies. Ongoing clinial trials are being performed to investigate the efficiency of HDACIs in human cancers. We have reviewed the current knowledge about the molecular mechanisms of action of HDACIs and the outcome of clinical studies using HDACIs in the therapy of several cancers.

Antioxidants & Redox Signaling, 2012

Significance: Histone deacetylase inhibitors (HDACIs) have emerged as a new class of anticancer therapeutics. The hydroxamic acid, suberoylanilide hydroxamic acid (Vorinostat, ZolinzaÔ), and the cyclic peptide, depsipeptide (Romidepsin, IstodaxÔ), were approved by the U.S. Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma in 2006 and 2009, respectively. At least 15 HDACIs are currently undergoing clinical trials either alone or in combination with other therapeutic modalities for the treatment of numerous hematological and solid malignancies. Recent Advances: The potential utility of HDACIs has been extended to nononcologic applications, including autoimmune disorders, inflammation, diseases of the central nervous system, and malaria. Critical Issues: Given the promise of HDACIs, there is growing interest in the potential of dietary compounds that possess HDAC inhibition activity. This review is focused on the identification of and recent findings with HDACIs from dietary, medicinal plant, and microbial sources. We discuss the mechanisms of action and clinical potential of natural HDACIs. Future Directions: Apart from identification of further HDACI compounds from dietary sources, further research will be aimed at understanding the effects on gene regulation on lifetime exposure to these compounds. Another important issue that requires clarification. Antioxid. Redox Signal. 17, 340-354.

Molecules

Cancer is a complex pathology that causes a large number of deaths worldwide. Several risk factors are involved in tumor transformation, including epigenetic factors. These factors are a set of changes that do not affect the DNA sequence, while modifying the gene’s expression. Histone modification is an essential mark in maintaining cellular memory and, therefore, loss of this mark can lead to tumor transformation. As these epigenetic changes are reversible, the use of molecules that can restore the functions of the enzymes responsible for the changes is therapeutically necessary. Natural molecules, mainly those isolated from medicinal plants, have demonstrated significant inhibitory properties against enzymes related to histone modifications, particularly histone deacetylases (HDACs). Flavonoids, terpenoids, phenolic acids, and alkaloids exert significant inhibitory effects against HDAC and exhibit promising epi-drug properties. This suggests that epi-drugs against HDAC could preve...

Molecules, 2019

Histone deacetylases (HDACs) are enzymes that can control transcription by modifying chromatin conformation, molecular interactions between the DNA and the proteins as well as the histone tail, through the catalysis of the acetyl functional sites removal of proteins from the lysine residues. Also, HDACs have been implicated in the post transcriptional process through the regulation of the proteins acetylation, and it has been found that HDAC inhibitors (HDACi) constitute a promising class of pharmacological drugs to treat various chronic diseases, including cancer. Indeed, it has been demonstrated that in several cancers, elevated HDAC enzyme activities may be associated with aberrant proliferation, survival and metastasis. Hence, the discovery and development of novel HDACi from natural products, which are known to affect the activation of various oncogenic molecules, has attracted significant attention over the last decade. This review will briefly emphasize the potential of natur...

Nutrients, 2018

Cancer initiation and progression are the result of genetic and/or epigenetic alterations. Acetylation-mediated histone/non-histone protein modification plays an important role in the epigenetic regulation of gene expression. Histone modification is controlled by the balance between histone acetyltransferase and (HAT) and histone deacetylase (HDAC) enzymes. Imbalance between the activities of these two enzymes is associated with various forms of cancer. Histone deacetylase inhibitors (HDACi) regulate the activity of HDACs and are being used in cancer treatment either alone or in combination with other chemotherapeutic drugs/radiotherapy. The Food and Drug Administration (FDA) has already approved four compounds, namely vorinostat, romidepsin, belinostat, and panobinostat, as HDACi for the treatment of cancer. Several other HDACi of natural and synthetic origin are under clinical trial for the evaluation of efficiency and side-effects. Natural compounds of plant, fungus, and actinomy...