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      Arsenic Disulfide Promoted Hypomethylation by Increasing DNA Methyltransferases Expression in Myelodysplastic Syndrome

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          Abstract

          Background

          Previous studies have shown that DNA methylation plays a significant role in myelodysplastic syndrome (MDS). In addition to hypermethylation, aberrant hypomethylation can result in the transcriptional activation of oncogenes in cancer, including MDS. Therefore, drugs targeting DNA hypomethylation are needed for the treatment of MDS. This study aimed to investigate whether As 2S 2 promoted hypomethylation by increasing DNA methyltransferases (DNMTs) expression in MDS.

          Patients and Methods

          Ten bone marrow samples from MDS patients and 3 healthy donors were obtained for the examination of the DNA methylation with a Human Methylation 850K BeadChip. The mRNA expressions for the DNMTs in the ten MDS patients and 3 controls were compared by Q-PCR. Then, the MDS cell line SKM-1 was treated with As 2S 2. After 2 days of treatment, Human Methylation 850K BeadChip was applied to analyze the changes of gene methylation status in the cells. Q-PCR and Western blot were taken to test the changes of mRNA and protein expressions for DNMTs in SKM-1 cells after treatment.

          Results

          Five hundred ninety-two abnormally hypomethylated genes were found in MDS patients compared to those in controls by Human Methylation 850K. The mRNA expressions of DNMTs (DNMT1, DNMT3a and DNMT3b) in MDS patients were significantly lower than those in healthy individuals. The IC50 value of As 2S 2 for SKM-1 cells was 4.97 μmol/L.Treatment with As 2S 2 at 2 μmoL/L resulted in significant alterations in the methylation levels at 1718 sites in SKM-1 cells compared to those in the controls. Hypermethylation was observed in 1625 sites (94.58%), corresponding to 975 genes, compared to those in the controls. Finally, the expression levels of DNMTs (DNMT1, DNMT3a, and DNMT3b) significantly increased in SKM-1 cells treated with As 2S 2 at 2 μmoL/L and 4 μmoL/L.

          Conclusion

          These data show a potential clinical application of As 2S 2 as an innovative hypermethylation agent in MDS.

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          Most cited references 32

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          Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

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            Chromosomal instability and tumors promoted by DNA hypomethylation.

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              Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands.

              We have recently identified glucose-regulated protein-78 (GRP78) as a relevant molecular target expressed in metastatic tumors by fingerprinting the circulating repertoire of antibodies from cancer patients. Here we design and evaluate a ligand-receptor system based on the tumor cell membrane expression of GRP78. We show that GRP78 binding peptide motifs target tumor cells specifically in vivo and in human cancer specimens ex vivo. Moreover, synthetic chimeric peptides composed of GRP78 binding motifs fused to a programmed cell death-inducing sequence can suppress tumor growth in xenograft and isogenic mouse models of prostate and breast cancer. Together, these preclinical data validate GRP78 on the tumor cell surface as a functional molecular target that may prove useful for translation into clinical applications.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                30 April 2020
                2020
                : 14
                : 1641-1650
                Affiliations
                [1 ]China Academy of Chinese Medical Sciences, Institute of Geriatric Medicine, Xiyuan Hospital , Beijing, People’s Republic of China
                [2 ]Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences , Beijing, People’s Republic of China
                Author notes
                Correspondence: Xiao-Mei Hu Department of Hematology, Xiyuan Hospital, China Academy of Chinese Medical Sciences , Xiyuan Playground No. 1, Haidian District, Beijing100091, People’s Republic of ChinaTel +86 186 1035 0593 Email huxiaomei_2@163.com
                Article
                239158
                10.2147/DDDT.S239158
                7201013
                © 2020 Zhou et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 7, Tables: 2, References: 38, Pages: 10
                Categories
                Original Research

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