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      Indirubin suppresses ovarian cancer cell viabilities through the STAT3 signaling pathway

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          Abstract

          Background

          Indirubin is the active component of Danggui Longhui Wan, a traditional Chinese medicine formulation. Due to its anti-inflammation and anti-tumor effects, indirubin has been widely used for the treatment of inflammation, cancer, and other chronic disease. Herein, we aimed to investigate the role and mechanism of indirubin in human ovarian cancer cell proliferation.

          Materials and methods

          The cell viability was determined by Cell Counting Kit-8 and colony formation assays by treatment with different dosages of indirubin over 72 hours. Apoptosis was examined by flow cytometry with fluorescein isothiocyanate Annexin V Apoptosis Detection Kit. Western blot assay was finally applied to analyze the expression of cancer-related STAT3 pathway and its downstream proteins.

          Results

          Indirubin was found to significantly inhibit cell viability and induce apoptosis in 2 human ovarian cancer cell lines. Mechanistic studies revealed that indirubin treatment led to reduced levels of phosphorylated-STAT3, thus repressing the downstream pro-survival proteins and elevating pro-apoptosis ones.

          Conclusion

          Our study provided the evidence for anti-survival activity of indirubin by inhibiting cell viability and inducing apoptosis in human ovarian cancer cells, which involved impaired STAT3 signaling pathway. Our findings further support indirubin as a potential drug candidate against human ovarian cancer.

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          Most cited references 21

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          Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention.

          The signal transducers and activators of transcription (STAT)factors function as downstream effectors of cytokine and growth factor receptor signaling. Compared with normal cells and tissues, constitutively activated STATs have been detected in a wide variety of human cancer cell lines and primary tumors. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulated process. In tumor cells, constitutive activation of STATs is linked to persistent activity of tyrosine kinases, including Src, epidermal growth factor receptor, Janus kinases, Bcr-Abl, and many others. Such oncogenic tyrosine kinases are often activated as a consequence of permanent ligand/receptor engagement in autocrine or paracrine cytokine and growth factor signaling or represent autonomous constitutively active enzymes as a result of genetic alterations found in tumor but not normal cells. Persistent signaling of specific STATs, in particular Stat3 and Stat5, has been demonstrated to directly contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis. STATs participate in oncogenesis through up-regulation of genes encoding apoptosis inhibitors and cell cycle regulators such as Bcl-x(L), Mcl-1, cyclins D1/D2, and c-Myc. Inhibition of constitutively active STAT signaling pathways has been shown repeatedly to inhibit tumor cell growth in vitro and in vivo and provides a novel means for therapeutic intervention in human cancer. In this review, we will: (a) explain the mechanisms of STAT activation in normal and malignant signaling; (b) summarize recent evidence for the critical role of constitutively activated Stat3 and Stat5 in oncogenesis; (c) identify candidate STAT target genes implicated in tumor progression; and (d) discuss molecular and pharmacological strategies to interfere with STAT signaling for potential therapeutic intervention in human cancer.
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            Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases.

            Indirubin is the active ingredient of Danggui Longhui Wan, a mixture of plants that is used in traditional Chinese medicine to treat chronic diseases. Here we identify indirubin and its analogues as potent inhibitors of cyclin-dependent kinases (CDKs). The crystal structure of CDK2 in complex with indirubin derivatives shows that indirubin interacts with the kinase's ATP-binding site through van der Waals interactions and three hydrogen bonds. Indirubin-3'-monoxime inhibits the proliferation of a large range of cells, mainly through arresting the cells in the G2/M phase of the cell cycle. These results have implications for therapeutic optimization of indigoids.
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              Plants used against cancer - an extension of the work of Jonathan Hartwell.

              A survey of plants used ethnomedically against cancer was undertaken, using the NAPRALERT database currently maintained by the Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois-Chicago. We report over 350 species which are reported to be used against cancer and not cited in the work of Jonathan Hartwell, "Plants used against cancer: a survey", including previously unrepresented genera and families.
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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
                04 October 2018
                : 12
                : 3335-3342
                Affiliations
                Department of Obstetrics and Gynecology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China, jifenhu_fj@ 123456126.com
                Author notes
                Correspondence: Jifen Hu, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Fujian Medical University, No 20 Chazhong Road, Fuzhou, Fujian, 350005, China, Tel/fax +86 05 918 798 3333, Email jifenhu_fj@ 123456126.com
                Article
                dddt-12-3335
                10.2147/DDDT.S174613
                6174913
                © 2018 Chen 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

                indirubin, ovarian cancer, cell viability, stat3 signaling

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