Chaetocin

Chaetocin, a natural thiodioxopiperazine product from Chaetomium species, is a lysine-specific histone methyltransferase inhibitor, which reduces the histone methyltransferase effects of SUV39H1 with IC50 value of 0.8 μM.
SUV39H1 is a histone methyltransferase that can methylate Lys-9 of histone H3 and plays an important role in many processes including repression of MYOD1-stimulated differentiation, regulation of the cell cycle and celll differentiation, and regulation of telomere length.
Chaetocin was found to have apoptotic effects on some cancer cells. In patient CD138+ myeloma cells, chaetocin has the potent antimyeloma activity which is attributable to reactive oxygen species (ROS) induction imposed by inhibition of the redox enzyme thioredoxin reductase [1].  Chaetocin reduced the methylation of H3K9 and H3K27 in HL-60 and KG-1a cells [2].
The component has also been used in animal models to study the role of SUV39H1. This component exhibits anti-proliferative activity and anti-cancer effect in a mouse myeloma xenografts model [3].
References:
1.Isham CR, Tibodeau JD, Jin W, Xu R, Timm MM, Bible KC. Chaetocin: a promising new antimyeloma agent with in vitro and in vivo activity mediated via imposition of oxidative stress. Blood 2007,109:2579-2588.
2.Lai YS, Chen JY, Tsai HJ, Chen TY, Hung WC. The SUV39H1 inhibitor chaetocin induces differentiation and shows synergistic cytotoxicity with other epigenetic drugs in acute myeloid leukemia cells. Blood Cancer J 2015,5:e313.
3.Isham CR, Tibodeau JD, Bossou AR, Merchan JR, Bible KC. The anticancer effects of chaetocin are independent of programmed cell death and hypoxia, and are associated with inhibition of endothelial cell proliferation. Br J Cancer 2012,106:314-323.

The histone 3 lysine 9 methyltransferase inhibitor chaetocin improves prognosis in a rat model of high salt diet-induced heart failure.[Pubmed:28051130]

Sci Rep. 2017 Jan 4;7:39752.

Histone acetylation has been linked to cardiac hypertrophy and heart failure. However, the pathological implications of changes in histone methylation and the effects of interventions with histone methyltransferase inhibitors for heart failure have not been fully clarified. Here, we focused on H3K9me3 status in the heart and investigated the effects of the histone H3K9 methyltransferase inhibitor Chaetocin on prognoses in Dahl salt-sensitive rats, an animal model of chronic heart failure. Chaetocin prolonged survival and restored mitochondrial dysfunction. ChIP-seq analysis demonstrated that chronic stress to the heart induced H3K9me3 elevation in thousands of repetitive elements, including intronic regions of mitochondria-related genes, such as the gene encoding peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. Furthermore, Chaetocin reversed this effect on these repetitive loci. These data suggested that excessive heterochromatinization of repetitive elements of mitochondrial genes in the failing heart may lead to the silencing of genes and impair heart function. Thus, Chaetocin may be a potential therapeutic agent for chronic heart failure.

Effect of chaetocin on renal cell carcinoma cells and cytokine-induced killer cells.[Pubmed:27141211]

Ger Med Sci. 2016 Apr 18;14:Doc04.

We examined the cytotoxic effects of Chaetocin on clear cell renal cell carcinoma (ccRCC) cells and the possibility to combine the effects of Chaetocin with the effects of cytokine-induced killer cells (CIK) assayed by MTT assay and FACS analysis. Chaetocin is a thiodioxopiperazine produced by fungi belonging to the chaetomiaceae family. In 2007, it was first reported that Chaetocin shows potent and selective ex vivo anti-cancer activity by inducing reactive oxygen species. CIK cells are generated from CD3+/CD56- T lymphocytes with double negative CD4-/CD8- phenotype that are isolated from human blood. The addition of distinct interleukins and antibodies results in the generation of CIK cells that are able to specifically target and destroy renal carcinoma cells. The results of this research state that the anti-ccRCC activity of Chaetocin is weak and does not show a high grade of selectivity on clear cell renal cell carcinoma cells. Although the CIK cells show a high grade of selective anti-ccRCC activity, this effect could not be improved by the addition of Chaetocin. So Chaetocin seems to be no suitable agent for specific targeting ccRCC cells or for the combination therapy with CIK cells in renal cancer.

Chaetocin reactivates the lytic replication of Epstein-Barr virus from latency via reactive oxygen species.[Pubmed:28063010]

Sci China Life Sci. 2017 Jan;60(1):66-71.

Oxidative stress, regarded as a negative effect of free radicals in vivo, takes place when organisms suffer from harmful stimuli. Some viruses can induce the release of reactive oxygen species (ROS) in infected cells, which may be closely related with their pathogenicity. In this report, Chaetocin, a fungal metabolite reported to have antimicrobial and cytostatic activity, was studied for its effect on the activation of latent Epstein-Barr virus (EBV) in B95-8 cells. We found that Chaetocin remarkably up-regulated EBV lytic transcription and DNA replication at a low concentration (50 nmol L(-1)). The activation of latent EBV was accompanied by an increased cellular ROS level. N-acetyl-L-cysteine (NAC), an ROS inhibitor, suppressed Chaetocin-induced EBV activation. Chaetocin had little effect on histone H3K9 methylation, while NAC also significantly reduced H3K9 methylation. These results suggested that Chaetocin reactivates latent EBV primarily via ROS pathways.

Chaetocin-A histone methyltransferase inhibitor-Impairs proliferation, arrests cell cycle and induces nucleolar disassembly in Trypanosoma cruzi.[Pubmed:28185826]

Acta Trop. 2017 Jun;170:149-160.

The Trypanosomatidae family includes pathogenic species of medical and veterinary interest. Chagas disease is endemic in Latin America, and about 8 million people are infected worldwide. There is a need for more effective drugs for the acute, undetermined and chronic phases of the disease that, in addition, do not cause side effects, stimulating the search for identification of new drug targets, as well as new chemotherapeutic targets. Trypanosomatids contain characteristic structures, such as the nucleus that undergoes a closed mitosis without chromosome formation and variations of chromatin packing in the different protozoa developmental stages. The nuclear DNA is condensed by histones that suffer post-translational modifications, such as addition of methyl groups by histone methyltransferases (MHT) and addition of acetyl groups by acetyltransferases. These processes modulate gene expression and chromatin organization, which are crucial to transcription, replication, repair and recombination. In the present study, the effects of Chaetocin, a HMT inhibitor, on T. cruzi epimastigote proliferation, viability, ultrastructure and cell cycle were investigated. Results indicate that Chaetocin promoted irreversible inhibition of protozoa growth, evident unpacking of nuclear heterochromatin and intense nucleolus fragmentation, which is associated with parasite cell cycle arrest and RNA transcription blockage. Taken together, data obtained with Chaetocin treatment stimulate the use of histone methyltransferase inhibitors against pathogenic trypanosomatids.

Chaetocin is a specific inhibitor of the histone methyltransferase (HMT) SU(VAR)3-9 with an IC50 of 0.6 μM for SU(VAR)3-9. It also inhibits thioredoxin reductase (TrxR) with an IC50 of 4 μM.

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