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DNA Methylation and Epigenetics: New Developments in Biology and Treatment
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Jesus Duque, Michael Lübbert, Mark Kirschbaum
Another silencing histone methylation mark with relationship to DNA methylation activity is at H3K27 (103). The complexes that bring about this methylation share an EZH2 enzyme, part of the polycomb group (PcG) of proteins, which have an important role in silencing the Hox transcription factors, which as described earlier, are critical modulators of development and angiogenesis (104). Methylated H3K27 leads to further repression through binding of other PcG proteins, as well as specific interaction with all three DNMT (76). This EZH2-based relationship between H3K27 and DNA methylation appears to be particularly marked in cancers as opposed to normal tissue (105). Thus it is indicative of the complexity of attempting epigenetic therapy, that treatment of leukemia cells with the hydroxamic acid HDACi LBH589 led to depletion of EZH2 and decreased histone methylation of H3K27 (65).
Pesticides and Chronic Diseases
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
On the other hand, growing progress has been made in the recognition of epigenetic modifications in human chronic diseases, particularly cancer. Cancer is now considered as an epigenetic disease, the same as a genetic disease. There is tremendous evidence on the contribution of epigenetic events in the initiation, promotion, and progression of different types of cancers, mainly through silencing of tumor suppressor genes and/or activation of proto-oncogenes. These modifications have allocated such a fundamental role in cancer development that epigenetic therapy of cancer is rapidly growing in medical sciences.1124 In addition, epigenetic changes currently have been a powerful tool for studying the carcinogenesis mechanisms of occupational and environmental exposures.1125 The first note on pesticide-induced carcinogenesis through epigenetic mechanisms was from a study carried out by Maslansky and colleagues in 1981. They reported hepatocarcinogenesis of organochlorine pesticides with no genotoxic effects in hepatocytes and suspected to epigenetic modifications disrupting intracellular communications.1126 Later, reports presented about epigenetic actions of vinclozolin, a fungicide known to be an environmental endocrine disruptor, in association with adult-onset diseases, particularly tumor development.1127 Pesticides were introduced as carcinogens acting through epigenetic or nongenotoxic mechanisms.752
Treatments and Challenges
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
A variety of compounds containing diverse pharmacological activities has been acquired from different plant sources throughout the ages [1319]. Many important drugs used today, such as morphine and, more recently, paclitaxel and artemisinin, were derived from plants [1319]. Dietary phytochemicals continue to garner attention as potential chemopreventative or therapeutic, agents [1299, 1320, 1321]. A multitude of plant-derived chemicals have been documented in a variety of preclinical and clinical reports involving different types of cancer including two of the most common types, breast and prostate cancer (Tables 4.1 and 4.2) [1558–1560]. Phytochemicals and nutrients are known to modulate the epigenome through the regulation of pathways, networks, and mechanisms related to chromatin remodeling, nucleic acid and protein modifications, and other effects [366, 1322] (Figure 4.3). Bioactive food components can also directly influence the enzymes linked to epigenetic mechanisms [1322, 1323]. For example, curcumin inhibits histone acetyltransferases (HATs), genistein influences DNA methyltransferases (DNMTs), resveratrol, butyrate, sulforaphane, and diallyl sulfide inhibit histone deacetylase (HDAC), quercetin affects acetylation and phosphorylation, diindolylmethane affects histone acetylation, S-allyl mercaptocysteine and diallyl disulfide affect histone acetylation), and resveratrol, diindolylmethane, curcumin, genistein, and lignans affect miRNAs [7, 366, 1324–1327]. Despite the positive outcome of epigenetic therapy in the treatment of hematological malignancies, little to no favorable outcome has been accomplished in solid tumor treatment [365]. However, there is optimism for the future as we gain a greater understanding of epigenetic plasticity and restriction and apply these understandings to improve our ability to detect early epigenetic lesions, as well as to evaluate tumor stage and heterogeneity [283, 1328, 1329].
Efficacy and safety of an HDACi- and HMA-based protocol in adults with acute myeloid leukemia of intermediate- and adverse-risk categories: a retrospective study
Published in Hematology, 2023
Zhibo Guo, Dan Guo, Desheng Kong, Sicheng Bian, Leilei Lin, Shengjin Fan, Qi Li, Yanqiu Zhao, Yanmeng Jiang, Jiangrong Yan, Zheren Wang, Lili Sun, Yinghua Li
Achieving remission is crucial for patients with newly diagnosed or R/R AML to increase ORR and enhance survival benefits in patients, as well as for consolidation treatments or HSCT. Epigenetic therapy has widely attracted attention for the treatment of cancers in recent years. Hypomethylating agents (HMAs) such as decitabine and azacitidine were used for elder AML or adverse risk MDS patients. Interestingly, regimens of HMA combined with DA, HAAG, CAG and FLAG have shown better effect in R/R or de novo AML in clinical trials [16–18,34,35]. Hypomethylating agents or low dose- cytarabine combined with BCL-2 inhibitor has become promising regimen for AML patients intolerant for intensive chemotherapy, while there were also limitations in treating resistance or AML relapse [36]. Chidamide has shown significant inhibition of AML cell lines and exerted synergistic effects with HMAs [37,38]. A phase II study on chidamide combined with decitabine and CAG in patients with relapsed/refractory acute myeloid leukemia has shown tolerated and effective outcomes [39]. Chidamide also has been reported to overcome venetoclax plus azacitidine regimen-resistant AML [40], and increase the sensitivity of refractory or relapsed AML cells to anthracyclines [41]. Therefore, chidamide combined with HMA and chemotherapy seems to have great potential for AML patients especially resistant to conventional chemotherapy or targeted therapy.
Epigenetic Effects of Blackberry Extract on Human Colorectal Cancer Cells
Published in Nutrition and Cancer, 2022
Mohsen Tatar, Masoumeh Varedi, Fakhraddin Naghibalhossaini
Since DNMTs and HDACs have been implicated in malignant transformation in human cancers, targeting these enzymes have become an attractive therapeutic approach for anticancer therapy (10,17,48). Although numerous epigenetic modifiers including synthetic inhibitors of histone deacetylation and DNA methylation have shown anticancer activity in preclinical and clinical studies, due to their high toxicity and low efficiency, only a few of them have been approved for cancer treatment (48). Therefore, dietary bioactive compounds have been taken much attention as safer choice for epigenetic therapy for cancer (49). Many data have validated the anti-carcinogenic properties of different types of berries or their bioactive compounds, yet studies reporting their effect as epigenetic modifier are limited. The results of this study provide evidence supporting the epigenetic mechanisms contributing to their anticancer activity. Blackberry is one of the most polyphenol-rich fruits that contains many bioactive phytochemicals, such as anthocyanin and other flavonoids. The main advantage of using whole fruits or their full extract vs. the isolated compounds is the synergistic relationship between multiple bioactive components that may affect multiple biological pathways in cancer cells (50). Studies in our lab are ongoing to determine the berry bioactive components with epigenetic impacts on cancer cells.
Epigenetic regulation in Alzheimer’s disease: is it a potential therapeutic target?
Published in Expert Opinion on Therapeutic Targets, 2021
Epigenetic therapy consists of the use of drugs or other epigenome-influencing techniques to alter gene expression levels and treat medical conditions, and primarily involves inhibitors of enzymes that catalyze DNA methylation and histone tail modifications for the treatment of human cancers [9]. However, epigenetic therapy is largely investigated in animal models, cell culture models, and clinical trials of other diseases than cancer, including neurodegenerative disorders [10]. This article examines the epigenetic modifications observed in AD tissues, and particularly the changes in DNA methylation and histone tail modifications, discussing their role as potential therapeutic targets. The relevant articles discussed in the manuscript have been retrieved through a PubMed search between 2003 and 2021, including the terms ‘Alzheimer’s disease’ and ‘DNA methylation’, ‘histone tail modifications’, ‘epigenetics’, ‘epigenome-wide’, ‘whole-methylation analysis’, ‘epigenetic drugs’, ‘S-adenosylmethionine’, ‘inhibitors of histone deacetylases’, ‘inhibitors of DNA methyltransferases’, ‘animal models’, ‘epigenetic therapy’.