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dc.creatorTovilović-Kovačević, Gordana
dc.creatorKrstić-Milošević, Dijana
dc.creatorVinterhalter, Branka
dc.creatorToljić, Mina
dc.creatorPerović, Vladimir
dc.creatorTrajković, Vladimir
dc.creatorHarhaji Trajković, Ljubica
dc.creatorZogović, Nevena
dc.date.accessioned2018-08-16T09:45:20Z
dc.date.available2900-01-01
dc.date.issued2018
dc.identifier.urihttps://www.sciencedirect.com/science/article/pii/S0944711318300874?via%3Dihub
dc.identifier.urihttps://ibiss-r.rcub.bg.ac.rs/handle/123456789/3125
dc.description.abstractBACKGROUND Glioblastoma multiforme (GMB) is the most malignant of all brain tumors with poor prognosis. Anticancer potential of xanthones, bioactive compounds found in Gentiana dinarica, is well-documented. Transformation of G. dinarica roots with Agrobacterium rhizogenes provides higher xanthones accumulation, which enables better exploitation of these anticancer compounds. HYPOTHESIS/PURPOSE The aim of this study was to investigate antiglioma effect of three different G. dinarica extracts: E1—derived from untransformed roots, E2—derived from roots transformed using A. rhizogenes strain A4M70GUS, and E3—derived from roots transformed using A. rhizogenes strain 15834/PI. Further, mechanisms involved in anticancer potential of the most potent extract were examined in detail, and its active component was determined. METHODS The cell viability was assessed using MTT and crystal violet test. Cell cycle analysis, the expression of differentiation markers, the levels of autophagy, and oxidative stress were analyzed by flow cytometry. Autophagy and related signaling pathways were assessed by immunoblotting. RESULTS E3, in contrast to E1 and E2, strongly reduced growth of U251 human glioblastoma cells, triggered cell cycle arrest in G2/M phase, changed cellular morphology, and increased expression of markers of differentiated astrocytes (glial fibrillary acidic protein) and neurons (β-tubulin). E3 stimulated autophagy, as demonstrated by enhanced intracellular acidification, increased microtubule-associated light chain 3B (LC3-I) conversion to autophagosome associated LC3-II, and decreased level of selective autophagy target p62. Induction of autophagy was associated with Akt-dependent inhibition of main autophagy suppressor mammalian target of rapamycin (mTOR). Both genetic and pharmacological inhibition of autophagy suppressed the expression of differentiation markers, but had no effect on cell cycle arrest in E3-treated cells. E3 stimulated oxidative stress, and antioxidants vitamin E and N-acetyl cysteine inhibited autophagy and differentiation of E3-treated U251 cells. The most prevalent compound of E3, xanthone aglycone norswertianin, also arrested glioblastoma cell proliferation in G2/M phase and induced glioblastoma cell differentiation through induction of autophagy and oxidative stress. CONCLUSION These results indicate that E3 and its main active component norswertianin may serve as a potential candidate for differentiation therapy of glioblastoma.
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173053/RS//
dc.relationinfo:eu-repo/grantAgreement/MESTD/Integrated and Interdisciplinary Research (IIR or III)/41025/RS//
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/173015/RS//
dc.rightsrestrictedAccess
dc.sourcePhytomedicine
dc.subjectGentiana dinarica transformed roots
dc.subjectXanthone
dc.subjectNorswertianin
dc.subjectGlioblastoma
dc.subjectCell differentiation
dc.subjectAutophagy
dc.titleXanthone-rich extract from Gentiana dinarica transformed roots and its active component norswertianin induce autophagy and ROS-dependent differentiation of human glioblastoma cell line
dc.typearticleen
dc.rights.licenseARR
dcterms.abstractТовиловић-Ковачевић, Гордана; Крстић-Милошевић, Дијана; Винтерхалтер, Бранка; Трајковић, Владимир; Тољић, Мина; Перовић, Владимир; Хархаји Трајковић, Љубица; Зоговић, Невена;
dc.rights.holder© 2018 Elsevier GmbH
dc.citation.volume47
dc.identifier.doi10.1016/J.PHYMED.2018.03.052
dc.identifier.scopus2-s2.0-85050886777
dc.identifier.wos000442764100016
dc.citation.apaTovilovic-Kovacevic, G., Krstic-Milosevic, D., Vinterhalter, B., Toljic, M., Perovic, V., Trajkovic, V., … Zogovic, N. (2018). Xanthone-rich extract from Gentiana dinarica transformed roots and its active component norswertianin induce autophagy and ROS-dependent differentiation of human glioblastoma cell line. Phytomedicine, 47, 151–160.
dc.citation.vancouverTovilovic-Kovacevic G, Krstic-Milosevic D, Vinterhalter B, Toljic M, Perovic V, Trajkovic V, Harhaji-Trajkovic L, Zogovic N. Xanthone-rich extract from Gentiana dinarica transformed roots and its active component norswertianin induce autophagy and ROS-dependent differentiation of human glioblastoma cell line. Phytomedicine. 2018;47:151–60.
dc.citation.spage151
dc.citation.epage160
dc.type.versionpublishedVersionen
dc.citation.rankaM21


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