31
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Juglone induces apoptosis of tumor stem-like cells through ROS-p38 pathway in glioblastoma

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Juglone is a natural pigment, which has cytotoxic effect against various human tumor cells. However, its cytotoxicity to glioma cells, especially to tumor stem-like cells (TSCs) has not been demonstrated.

          Methods

          TSCs of glioma were enriched from U87 and two primary cells (SHG62, and SHG66) using serum-free medium supplemented with growth factors, including bFGF, EGF and B27. After treatment of juglone with gradient concentrations (0, 10, 20, and 40 μM), the viability and apoptosis of TSCs were evaluated by WST-8 assay and flow cytometry. Reactive oxygen species (ROS) was labeled by the cell-permeable fluorescent probe and detected with flow cytometry. ROS scavenger (NAC) and p38-MAPK inhibitor (SB203580) were applied to resist the cytotoxic effect. Caspase 9 cleavage and p38 phosphorylation (P-p38) were quantified by western blot. Juglone as well as temozolomide (TMZ) were administrated in intracranial xenografts and MR scan was performed every week to evaluate the anti-tumor effect in vivo.

          Results

          Juglone could obviously inhibit the proliferation of TSCs in glioma by decreasing cell viability ( P < 0.01) and inducing apoptosis ( P < 0.01), which was accompanied by increased caspase 9 cleavage in a dose-dependent manner ( P < 0.01). In the meantime, juglone could generate ROS significantly and increase p38 phosphorylation ( P < 0.01). In addition, pretreatment with ROS scavenger or p38-MAPK inhibitor could reverse juglone-induced cytotoxicity ( P < 0.01). More importantly, juglone could also suppress tumor growth in vivo and improve the survival of U87-bearing mice compared with control ( P < 0.05), although TMZ seemed to have better effect.

          Conclusions

          Juglone could inhibit the growth of TSCs in gliomas through the activation of ROS-p38-MAPK pathway in vitro, and the anti-glioma effect was validated in vivo, which offers a potential therapeutic agent to gliomas.

          Related collections

          Most cited references25

          • Record: found
          • Abstract: found
          • Article: not found

          A restricted cell population propagates glioblastoma growth following chemotherapy

          Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, with a median survival of about one year 1 . This poor prognosis is due to therapeutic resistance and tumor recurrence following surgical removal. Precisely how recurrence occurs is unknown. Using a genetically-engineered mouse model of glioma, we identify a subset of endogenous tumor cells that are the source of new tumor cells after the drug, temozolomide (TMZ), is administered to transiently arrest tumor growth. A Nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumor cells. Upon arrest of tumor cell proliferation with TMZ, pulse-chase experiments demonstrate a tumor re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumor growth and combined TMZ-ganciclovir treatment impeded tumor development. These data indicate the existence of a relatively quiescent subset of endogenous glioma cells that are responsible for sustaining long-term tumor growth through the production of transient populations of highly proliferative cells.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Patients With Proneural Glioblastoma May Derive Overall Survival Benefit From the Addition of Bevacizumab to First-Line Radiotherapy and Temozolomide: Retrospective Analysis of the AVAglio Trial.

            The AVAglio (Avastin in Glioblastoma) and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy plus temozolomide. To establish whether certain patient subgroups derived an OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy was assessed for each patient subgroup.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Isolation and characterization of cancer stem like cells in human glioblastoma cell lines.

              To identify and compare the features of stem like cells in human glioblastoma cell lines U251, U87MG, A172 with primary cultured glioblastoma stem cells, the ratio of CD133+ cells, the ability of tumor sphere formation, and self-renewing capacity of U251, U87MG, A172 cells in serum free medium plus EGF, bFGF and B27 supplement were detected. The results suggested that there might be more cancer stem like cells in U251 cells compared with others. CD133+ cells enriched in SP cells and in U251 cells cultured with the serum free medium. They expressed the neural stem cell markers CD133 and Nestin, but lacked of neuronal and astrocyte marker MAP2, beta-III tubulin and GFAP. They could apparently generate both neurons and glial cells after serum retrieved in vitro. Gli1, Bmi1, Notch2 and PTEN were also found expressed highly in them. Moreover, CD133+ cells were more resistant to hypoxia, irradiations and some chemotherapeutics than CD133-cells. So we suggested that glioblastoma stem like cells were existed in CD133+ cells in U251 cell line with characteristics of self-renew and generation of an unlimited progeny of non-tumorigenic cells. Molecular and functional characterization of such a tumorigenic population may be exploited in the development of novel cancer therapeutic drugs.
                Bookmark

                Author and article information

                Contributors
                wujinfeng21@163.com
                kexue168163@163.com
                xy1204@hotmail.com
                Jingwen419@outlook.com
                drweizhu@sina.com
                Zhangtang1218@vip.sina.com
                clclcl95@sina.com
                hs_glioma@126.com
                maoying@fudan.edu.cn
                Journal
                BMC Neurol
                BMC Neurol
                BMC Neurology
                BioMed Central (London )
                1471-2377
                7 April 2017
                7 April 2017
                2017
                : 17
                : 70
                Affiliations
                [1 ]GRID grid.8547.e, Department of Dermatology, Huashan Hospital, , Fudan University, ; #12 Middle Wurumuqi Road, Shanghai, 200040 People’s Republic of China
                [2 ]GRID grid.8547.e, Department of Neurosurgery, Huashan Hospital, , Fudan University, ; #12 Middle Wurumuqi Road, Shanghai, 200040 People’s Republic of China
                [3 ]GRID grid.8547.e, Institutes of Biomedical Sciences, , Fudan University, ; #131 Dong’an Road, Shanghai, 200040 People’s Republic of China
                [4 ]GRID grid.440208.a, Department of Ultrasound, , Hebei General Hospital, ; #348 West Heping Road, Shijiazhuang, Hebei Province 050000 People’s Republic of China
                [5 ]GRID grid.8547.e, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences and Institutes of Brain Science, , Fudan University, ; Shanghai, 200040 People’s Republic of China
                [6 ]GRID grid.8547.e, The Collaborative Innovation Center for Brain Science, , Fudan University, ; Shanghai, 200040 People’s Republic of China
                Article
                843
                10.1186/s12883-017-0843-0
                5383964
                28388894
                d538ff89-1627-4403-8bc5-2d5a4f160cbe
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 2 August 2016
                : 20 March 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100007225, Ministry of Science and Technology;
                Award ID: 2014DFA31470
                Award Recipient :
                Funded by: National Nature Science Foundation of China
                Award ID: 81611130223
                Award ID: 81572483
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002858, China Postdoctoral Science Foundation;
                Award ID: 2015M5815
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Neurology
                juglone,glioma,tumor stem-like cells,apoptosis,reactive oxygen species
                Neurology
                juglone, glioma, tumor stem-like cells, apoptosis, reactive oxygen species

                Comments

                Comment on this article