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Familial Monosomy 7 Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Treatment options for familial monosomy 7 syndrome consist of bone marrow transplantation (BMT, or allogeneic stem cell transplantation), and cytoreductive chemotherapy (e.g., demethylating agent 5-azacytidine, or imatinib for cytopenia) before transplant [26]. BMT is curative for monosomy 7 and should be performed ideally prior to the emergence of a leukemic clone [27,28].
Intrinsic and Extrinsic Factors That Influence Epigenetics
Published in Cristina Camprubí, Joan Blanco, Epigenetics and Assisted Reproduction, 2018
Ivan Nalvarte, Joëlle Rüegg, Carlos Guerrero-Bosagna
The first pharmacological agent used to deliberately alter the epigenome was the demethylating agent 5-AzaC. 5-AzaC was initially tested as a treatment against leukemia in mice (87) and is currently approved by the FDA (since 2004) for the chemotherapeutical treatment of the myelodysplastic syndrome (88). In addition to 5-AzaC, there are currently a number of other epigenetic drugs approved for clinical use by the FDA (89): Decitabine (5-aza-2′-deoxycytidine) is also a hypomethylating agent with similar therapeutic applications as 5-AzaC for the treatment of myelodysplastic syndrome; Tranylcypromine and phenelzine are lysine demethylase inhibitors initially approved as anti-depressants, but currently also tested for cancer treatment; Trichostatin-A, Vorinostat, Panobinostat, and Belinostat are HDAC inhibitors (of the hydroxamic acids group) employed in the treatment of lymphoma and leukemia; Mocetinostat is an HDAC inhibitor from the benzamides group also employed for the treatment of myelodysplastic syndrome; Romidepsin is an HDAC I and II inhibitor with cyclic tetrapeptide antibiotic and antineoplastic activity approved for the treatment of patients with cutaneous T-cell lymphoma, used after they have been administered with systemic therapy (89). In addition, three epigenetic drugs based on the action of miRNAs have entered clinical trials: Miravirsen and RG-101 for the treatment of hepatitis C, and MRX34 for the treatment of cancer (89). Table 6.2 summarizes the current status of pharmacological agents that alter the epigenome.
Changes in Gene Expression During Aging of Mammals
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
Whether or not the reactivation is due to demethylation of –CmCGG– sequences is not known. It is possible that the methylation status of –CCGG– sequences at critical sites of the gene may turn the gene ‘on’ or ‘off’. The demethylating agent, 5-azacytidine (AZT), a potent inhibitor of methylation, can reactivate genes in the inactive chromosome in somatic cell hybrids,81 and there is convincing evidence that X-chromosome inactivation is related to differential methylation of cytosine in the DNA of the two X-chromosomes.82 It would be interesting to find out which –CCGG– sequence(s) in the inactive OCT gene undergoes demethylation and whether this is due to an increase in the level of demethylase. Whatever the mechanism, it is clear that the reactivation of the gene is due to its destabilization by a random event. If such reactivation is random, it is difficult to comprehend how such events would cause ‘normal’ aging, because aging is more or less a gradual process. The normal mouse that does not have this mutation also ages. Hence, random destabilization or dysdifferentiation is unlikely to lead to ‘normal’ aging.
Efficacy of azacitidine in preventing relapse after hematopoietic stem cell transplantation for advanced myeloid malignancies: a systematic review and meta-analysis
Published in Expert Review of Hematology, 2022
Tingting Pan, Shiyu Han, Meng Zhou, Jiaqian Qi, Hong Wang, Xiaoyan Xu, Xueqian Li, Yifang Yao, Yue Han
AZA, a DNA demethylating agent, has shown clinical efficacy in the treatment of AML and MDS. AZA directly and irreversibly inhibits DNA methyltransferase when incorporated into DNA in the S phase at lower doses [26]. At high doses, AZA induces rapid DNA damage and is cytotoxic; at low doses, AZA induces DNA hypomethylation by covalently trapping and degrading the expression levels these proteins. AZA is proposed for use at a dose of 75 mg/m2 for 7 days of 28 days in a cycle for MDS as well as elderly AML patients ineligible for intensive chemotherapy. In a multicenter clinical trial in Germany, AZA was administered for the treatment of relapse at the same dose as induction therapy [27]. Craddock et al. showed that 25% of evaluable patients responded to azacitidine therapy who with recurrent disease after HSCT [28]. The 2-year overall survival rate in this population was 12%. Therefore, we must take preventive measures to improve the survival rate. There are various treatment options to prevent relapse after transplantation. Most of the studies included used AZA at a dose of 32 mg/kg/d for five consecutive days every 28 days, while some studies used other amounts. Several authors have proposed prophylactic treatment strategies aimed at eliminating residual malignant cells, which are undetectable by surveillance techniques currently available [6].
DNA methyltransferase inhibitors increase NOD-like receptor activity and expression in a monocytic cell line
Published in Immunopharmacology and Immunotoxicology, 2022
Claire L. Feerick, Declan P. McKernan
Relative to the untreated control group, priming with 5-Aza-dC increased iE-DAP-induced TNF-α from 2-fold to 9-fold (p < .001) and IL-6 from 1.9-fold to 12-fold (p < .001,). This demethylating agent also caused a greater impact on responses to TRI-DAP. Priming with 5-Aza-dC increased TRI-DAP-induced TNF-α from 3.3-fold to 12.4-fold (p < .001) and IL-6 from 2.8-fold to 29.3-fold (p < 0.001), as outlined in Figure 1(A,B). Similar results were also obtained with 5-aza (Supplemental Figure 1). Therefore, it appears that priming with a demethylating agent augments THP-1 pro-inflammatory activity following NOD1 stimulation. Stimulation of THP-1 cells with iE-DAP significantly increased TNF-α (2.2-fold, p < .001) and IL-6 (2.5-fold, p < .05) mRNA expression. TRI-DAP induced a similar pattern of events, increasing TNF-α (2.8-fold, p < .001) and IL-6 (4.5-fold, p < .001). SAHA treatment reduced basal levels of TNF-α (0.6-fold, p < .05). Relative to the untreated control group, priming with SAHA reduced iE-DAP-induced TNF-α from 2.2-fold to 0.8-fold (p < .001) and IL-6 from 2.5-fold to 1.8-fold (p>.05). SAHA priming also reduced TRI-DAP-induced TNF-α from 2.8-fold to 0.6-fold (p < .001) and IL-6 from 4.5-fold to 2.2-fold (p < .05), as shown in Figure 1(C,D).
Role of the BMP6 protein in breast cancer and other types of cancer
Published in Growth Factors, 2021
Andrea Marlene García Muro, Azaria García Ruvalcaba, Lourdes del Carmen Rizo de la Torre, Josefina Yoaly Sánchez López
In hepatocellular carcinoma and colorectal cancer, there have been discrepancies regarding BMP6 regulation. In Hepatocellular carcinoma, the tissue analysis by IHC revealed a strong BMP6 mRNA and protein expression compared to non-tumor tissue. While the expression of Alk2 is down-regulated in cell lines compared to primary human hepatocytes. Further analysis of HJV showed strongly reduced levels in the HCC cell lines compared to primary human hepatocytes. Together, the loss of Alk2 and HJV expression prevents the induction of hepcidin expression, avoiding downregulation of iron metabolism in patients with HCC (Maegdefrau et al. 2011). In contrast, it was found that in HCC patients’ samples, mRNA BMP6 levels were down-regulated in 85.85% of cases and had a worse prognosis, in addition to BMP6 lower expression in those with hypermethylation. Assays with the demethylating agent revealed that BMP6 expression levels were positively regulated after treatment, so DNA methylation can regulate BMP6 expression (He et al. 2014).