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Introduction to Cancer
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
DNA methylation and histone acetylation and de-acetylation are thought to play a role in epigenetic control by modulating transcription and chromatin condensation, respectively. These dynamic processes are regulated by enzymes known as methyltransferases and histone acetyltransferases and their counterparts, the histone de-acetylases. The equilibrium between them can be modified by exogenous influences known as epigenetic agents. These can modify methylation or acetylation and thus change the phenotypes of cells epigenetically, without their DNA sequences being altered. Some examples include chemicals such as bromobenzene and butyryl cyclic adenosine monophosphate, the hormone estradiol, and metals such as cadmium, arsenic, and nickel. In addition, radiation and reactive-oxygen species can act as epigenetic modifiers. Zebularine and 5-aza-2′-deoxycytidine, which are capable of inhibiting DNA methylation, are being used for the treatment of cancer (see Chapter 5) and are also being investigated as cancer chemopreventive agents (see Chapter 12).
Epigenetic regulation in Alzheimer’s disease: is it a potential therapeutic target?
Published in Expert Opinion on Therapeutic Targets, 2021
Other approaches to target DNA methylation are based on DNMT inhibitors (DNMTi), including azacitidine and decitabine that have been approved by the Food and Drug Administration (FDA) for the treatment of hematological malignancies, and other compounds such as guadecitabine, hydralazine, procaine, MG98, and zebularine that are being tested in hematological and solid tumors [96]. Monotherapy with these compounds has often shown an overall limited response in solid cancers, so that DNMTi are increasingly tested at low doses to reduce their toxicity and in combination with other epigenetic or standard anti-cancer therapies to reverse the acquired drug resistance of malignant cells and promote anti-tumor immune responses [96,97]. Indeed, these compounds seem more useful in rapidly proliferative cancer cells than in non-proliferative neurons, and their application in AD research is limited to a few studies that used azacitidine and decitabine in AD cell cultures mainly to demonstrate that the expression of certain genes is regulated by their promoter methylation, rather than as therapeutic approaches [51,98–100].
Promoter methylation of galanin receptors as epigenetic biomarkers for head and neck squamous cell carcinomas
Published in Expert Review of Molecular Diagnostics, 2019
Takeharu Kanazawa, Kiyoshi Misawa, Kazuya Shinmura, Yuki Misawa, Gen Kusaka, Mikiko Maruta, Toru Sasaki, Yusuke Watanabe, Thomas E. Carey
As epigenetic modifications have a reversible nature, such changes during carcinogenesis and progression would be valuable targets for cancer therapy. Recently, the development of epigenetic drugs has been making rapid advances. These drugs fall into two categories: DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis). Two DNMTis, 5-azacytidine and 5-aza-2′-deoxycytidine, are mainly applied in the clinical setting, and the development of numerous DNMTi agents is underway [88,89]. Data on therapeutic strategies using DNMTis for HNSCC are also accumulating. Zebularine, a kind of DNMTi, inhibits cell proliferation related to cell cycle arrest in HNSCC cell lines [90]. Promoter hypermethylation of tumor suppressor genes is a common event in HNSCC. Thus, the reactivation of methylated genes by DNA methyltransferase inhibitors is a promising method for the treatment of cancer, including HNSCC [91,92]. 5-Azacytidine can inhibit the growth of xenografted HNSCC tumors [93,94]. Furthermore, demethylation agents act as chemosensitizing agents against cancer. Decitabine reduces the overall dose requirements for cisplatin-induced apoptosis [95]. Demethylating agents such as 5-aza-2′-deoxycytidine induce global demethylation and also function as radiosensitizing agents for HNSCC treatment [96,97].
Emerging DNA methylation inhibitors for cancer therapy: challenges and prospects
Published in Expert Review of Precision Medicine and Drug Development, 2019
Aurora Gonzalez-Fierro, Alfonso Dueñas-González
Azacitidine and decitabine the oldest DNMTi are nucleoside analogs that intercalate with the DNA and upon their incorporation during S-phase of the cell cycle, form an irreversible complex with the DNMTs, leading to enzyme degradation. A limitation of these drugs is their short half-life of about 30 min which limits exposure of diseased cells to the drug, potentially abrogating their effectiveness [90,91]. On these bases, nucleoside analogs with longer half-lives are being sought that could theoretically improve response to therapy by enhancing incorporation of the active agent into dividing cells. Several novel nucleosides are in development. Zebularine, a less toxic cytidine analog was proven to be an effective and less toxic DNMTi in preclinical models. However, its clinical development was halted due to its extremely low bioavailability in rhesus monkeys [92].