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      Arsenic sulfide amplifies JQ1 toxicity via mitochondrial pathway in gastric and colon cancer cells

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          Abstract

          Purpose

          Gastric and colon cancers have been the leading causes of cancer mortality in the world with limited therapy. Small molecules binding to bromodomains of bromodomain-containing protein 4 (BRD4) exert strong antitumor activities against hematological malignancies, while generally have limited efficacy in advanced solid tumors. Here, we found that the bromodomain and extra-terminal (BET)-bromodomain inhibitor JQ1, when combined with arsenic sulfide (As 4S 4, abbreviated as AS), synergistically decreased the expression of nuclear factor of activated T-cells (NFATs) as well as the downstream oncogene c-Myc and largely induced cell apoptosis via mitochondrial pathway in gastric and colon cancer cell lines.

          Methods

          The synergistic cytotoxicity of AS and JQ1 in gastric and colon cancer cells was determined by MTT assay and verified by FACS assay. Western blot analysis and quantitative real-time PCR (qPCR) assay were used to detect the expression of NFATs and downstream apoptotic proteins. The mitochondrial transmembrane potential was determined by FACS assay, and the metastasis of cancer cells was detected by the wound-healing assay.

          Results

          AS and JQ1 synergistically induced cell apoptosis in gastric and colon cancer cells by downregulating NFATs and upregulating apoptotic proteins. Combination of AS and JQ1 was associated with the decreased mitochondrial transmembrane potential, the cytochrome c release, and the subsequent caspase-3 activation.

          Conclusion

          Thus, our data indicate that AS can effectively enhance the cytotoxicity of BET inhibitors in gastric and colon cancer cells through mitochondrial-mediated apoptosis induction.

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          Most cited references 26

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          Structure and ligand of a histone acetyltransferase bromodomain.

          Histone acetylation is important in chromatin remodelling and gene activation. Nearly all known histone-acetyltransferase (HAT)-associated transcriptional co-activators contain bromodomains, which are approximately 110-amino-acid modules found in many chromatin-associated proteins. Despite the wide occurrence of these bromodomains, their three-dimensional structure and binding partners remain unknown. Here we report the solution structure of the bromodomain of the HAT co-activator P/CAF (p300/CBP-associated factor). The structure reveals an unusual left-handed up-and-down four-helix bundle. In addition, we show by a combination of structural and site-directed mutagenesis studies that bromodomains can interact specifically with acetylated lysine, making them the first known protein modules to do so. The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase. Thus, the bromodomain is functionally linked to the HAT activity of co-activators in the regulation of gene transcription.
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            Sustained loss of a neoplastic phenotype by brief inactivation of MYC.

            Pharmacological inactivation of oncogenes is being investigated as a possible therapeutic strategy for cancer. One potential drawback is that cessation of such therapy may allow reactivation of the oncogene and tumor regrowth. We used a conditional transgenic mouse model for MYC-induced tumorigenesis to demonstrate that brief inactivation of MYC results in the sustained regression of tumors and the differentiation of osteogenic sarcoma cells into mature osteocytes. Subsequent reactivation of MYC did not restore the cells' malignant properties but instead induced apoptosis. Thus, brief MYC inactivation appears to cause epigenetic changes in tumor cells that render them insensitive to MYC-induced tumorigenesis. These results raise the possibility that transient inactivation of MYC may be an effective therapy for certain cancers.
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              BET bromodomain inhibition of MYC-amplified medulloblastoma.

              MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma. ©2013 AACR
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                14 November 2018
                : 12
                : 3913-3927
                Affiliations
                Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, siyu.chen@ 123456shsmu.edu.cn
                Author notes
                Correspondence: Siyu Chen, Department of Oncology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 1665 Kongjiang Road, Shanghai 200092, China, Tel +86 21 2507 7642, Email siyu.chen@ 123456shsmu.edu.cn
                [*]

                These authors contributed equally to this work

                Article
                dddt-12-3913
                10.2147/DDDT.S180976
                6241694
                © 2018 Tan 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.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                apoptosis, mitochondria, nfat, arsenic sulfide, jq1

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