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      Baicalin suppresses proliferation, migration, and invasion in human glioblastoma cells via Ca 2+-dependent pathway

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          Abstract

          Objective

          Baicalin, a kind of flavonoid extracted from the dry root of Scutellaria, possesses potent anticancer bioactivities in various tumor cell lines. Accumulating evidences show that baicalin induces autophagy and apoptosis to suppress the cancer growth. Moreover, the antineoplastic role of baicalin in human glioblastoma cells remains to be uncovered.

          Methods

          Both U87 and U251 human glioblastoma cell lines were employed in the present study. Cell viability was tested by Cell Counting Kit-8 and colony-forming assay; Flow cytometry was employed to analyze cell apoptosis, cell cycle, and Ca 2+ content. Cell immunofluorescence assays were used for analyzing terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), light chain 3 beta (LC3B), 5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanineiodide (JC-1), and Ca 2+ content. The protein levels were tested by Western blot. The SPSS software was used for statistical analysis.

          Results

          Baicalin suppressed the proliferation, migration, and invasion ability of human glioblastoma cells in a dose-dependent manner. Baicalin induced the loss of mitochondrial membrane potential and led to mitochondrial apoptosis. The maturation of microtubule-associated protein 1A/1B-LC3B indicated the activation of autophagy potentially through PI3K/Akt/mTOR pathway, and inhibition of autophagy by 3-methyladenine decreased the apoptotic cell ratio. Besides, baicalin increased the intercellular Ca 2+ content; meanwhile, chelation of free Ca 2+ by 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid inhibited both apoptotic and autophagy. Finally, baicalin suppressed tumor growth in vivo.

          Conclusion

          Our observations suggest that baicalin exerts cytotoxic effects on human glioblastoma cells by the autophagy-related apoptosis through Ca 2+ movement to the cytosol. Furthermore, baicalin has the potential as a candidate for the treatment of glioblastoma.

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          Most cited references 24

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          Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2.

          Macroautophagy is an evolutionary conserved lysosomal pathway involved in the turnover of cellular macromolecules and organelles. In spite of its essential role in tissue homeostasis, the molecular mechanisms regulating mammalian macroautophagy are poorly understood. Here, we demonstrate that a rise in the free cytosolic calcium ([Ca(2+)](c)) is a potent inducer of macroautophagy. Various Ca(2+) mobilizing agents (vitamin D(3) compounds, ionomycin, ATP, and thapsigargin) inhibit the activity of mammalian target of rapamycin, a negative regulator of macroautophagy, and induce massive accumulation of autophagosomes in a Beclin 1- and Atg7-dependent manner. This process is mediated by Ca(2+)/calmodulin-dependent kinase kinase-beta and AMP-activated protein kinase and inhibited by ectopic Bcl-2 located in the endoplasmatic reticulum (ER), where it lowers the [Ca(2+)](ER) and attenuates agonist-induced Ca(2+) fluxes. Thus, an increase in the [Ca(2+)](c) serves as a potent inducer of macroautophagy and as a target for the antiautophagy action of ER-located Bcl-2.
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            The biochemistry and medical significance of the flavonoids.

            Flavonoids are plant pigments that are synthesised from phenylalanine, generally display marvelous colors known from flower petals, mostly emit brilliant fluorescence when they are excited by UV light, and are ubiquitous to green plant cells. The flavonoids are used by botanists for taxonomical classification. They regulate plant growth by inhibition of the exocytosis of the auxin indolyl acetic acid, as well as by induction of gene expression, and they influence other biological cells in numerous ways. Flavonoids inhibit or kill many bacterial strains, inhibit important viral enzymes, such as reverse transcriptase and protease, and destroy some pathogenic protozoans. Yet, their toxicity to animal cells is low. Flavonoids are major functional components of many herbal and insect preparations for medical use, e.g., propolis (bee's glue) and honey, which have been used since ancient times. The daily intake of flavonoids with normal food, especially fruit and vegetables, is 1-2 g. Modern authorised physicians are increasing their use of pure flavonoids to treat many important common diseases, due to their proven ability to inhibit specific enzymes, to simulate some hormones and neurotransmitters, and to scavenge free radicals.
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              New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin.

              Traditional Chinese medicines have been recently recognized as a new source of anticancer drugs and new chemotherapy adjuvant to enhance the efficacy of chemotherapy and to ameliorate the side effects of cancer chemotherapies however their healing mechanisms are still largely unknown. Scutellaria baicalensis is one of the most popular and multi-purpose herb used in China traditionally for treatment of inflammation, hypertension, cardiovascular diseases, and bacterial and viral infections. Accumulating evidence demonstrate that Scutellaria also possesses potent anticancer activities. The bioactive components of Scutellaria have been confirmed to be flavones. The major constituents of Scutellaria baicalensis are Wogonin, Baicalein and Baicalin. These phytochemicals are not only cytostatic but also cytotoxic to various human tumor cell lines in vitro and inhibit tumor growth in vivo. Most importantly, they show almost no or minor toxicity to normal epithelial and normal peripheral blood and myeloid cells. The antitumor functions of these flavones are largely due to their abilities to scavenge oxidative radicals, to attenuate NF-kappaB activity, to inhibit several genes important for regulation of the cell cycle, to suppress COX-2 gene expression and to prevent viral infections. The tumor-selectivity of Wogonin has recently been demonstrated to be due to its ability to differentially modulate the oxidation-reduction status of malignant vs. normal lymphocytic cells and to preferentially induce phospholipase C gamma 1, a key enzyme involved in Ca(2+) signaling, through H(2)O(2) signaling in malignant lymphocytes. This review is aimed to summarize the research results obtained since the last 20 years and to highlight the recently discovered molecular mechanisms.
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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
                02 October 2018
                : 12
                : 3247-3261
                Affiliations
                [1 ]Department of Neurosurgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China, njhdwang@ 123456hotmail.com
                [2 ]Department of Neurosurgery, Jinling Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210002, China
                [3 ]Department of Neurosurgery, Jinling Hospital, Nanjing Medical University, Nanjing, Jiangsu 210002, China
                [4 ]Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
                Author notes
                Correspondence: Handong Wang, Department of Neurosurgery, Jinling Hospital, 305 East Zhongshan Road, Nanjing, Jiangsu 210002, China, Email njhdwang@ 123456hotmail.com
                [*]

                These authors contributed equally to this work

                Article
                dddt-12-3247
                10.2147/DDDT.S176403
                6173175
                © 2018 Zhu 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.

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                Original Research

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