The Mechanisms of In Vitro Cytotoxicity of Mountain Tea,
                        Sideritis scardica, against the C6 Glioma Cell Line

Ivica Jeremic; Vanja Tadic; Andjelka Isakovic; Vladimir Trajkovic; Ivanka Markovic; Zoran Redzic; Aleksandra Isakovic

doi:10.1055/s-0033-1350809

Planta Medica, Inhaltsverzeichnis

Planta Med 2013; 79(16): 1516-1524
DOI: 10.1055/s-0033-1350809

Biological and Pharmacological Activity

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

The Mechanisms of In Vitro Cytotoxicity of Mountain Tea, Sideritis scardica, against the C6 Glioma Cell Line

Autoren

Ivica Jeremic

¹Institute of Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia

²Institute of Rheumatology, Belgrade, Serbia
Vanja Tadic

³Institute for Medicinal Plant Research “Dr Josif Pančić”, Belgrade, Serbia
Andjelka Isakovic

¹Institute of Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia
Vladimir Trajkovic

⁴Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Belgrade, Serbia
Ivanka Markovic

¹Institute of Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia
Zoran Redzic

⁵Department of Physiology, Faculty of Medicine, Kuwait University, Safat, Kuwait
Aleksandra Isakovic

¹Institute of Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia

Abstract

Sideritis scardica (mountain tea) is an endemic plant on the Balkan Peninsula traditionally used for treating different conditions, mainly of inflammatory nature. This study was aimed to examine the cytotoxic activity of different S. scardica extracts against the rat glioma C6 line and rat astrocytes in primary culture. The obtained data revealed that diethyl ether (extract 2) and ethyl acetate (extract 3) extracts of S. scardica exerted a cytotoxic effect on C6 rat glioma cells. Diethyl ether extract induced an increase in reactive oxygen species production, leading to apoptotic and autophagic cell death. Ethyl acetate extract induced G₂ M cell cycle arrest and autophagy. None of the tested extracts was cytotoxic to rat astrocytes in primary culture. Cytotoxic effects of S. scardica extracts were, at least in part, mediated by their flavonoid constituents apigenin and luteolin that, when applied alone, induced cell cycle arrest, apoptosis, and autophagy.

Key words

Sideritis scardica - Lamiaceae - apigenin - luteolin - C6 glioma cells - autophagy

Volltext

Referenzen

References
1 González-Burgos E, Carretero ME, Gómez-Serranillos MP. Sideritis spp.: uses, chemical composition and pharmacological activities-a review. J Ethnopharmacol 2011; 135: 209-225
2 Petreska J, Stefova M, Ferres F, Moreno DA, Tomas-Berberan FA, Stefkov G, Kulevanova S, Gil-Izquierdo A. Potential bioactive phenolic of Macedonian Sideritis species used for medicinal “Mountain Tea”. Food Chem 2011; 125: 13-20
3 Demirtas I, Sahin A, Ayhan B, Tekin S, Telci I. Antiproliferative effects of the methanolic extracts of Sideritis libanotica Labill. subsp. linearis . Rec Nat Prod 2009; 3: 104-109
4 Tadić VM, Jeremic I, Dobric S, Isakovic A, Markovic I, Trajkovic V, Bojovic D, Arsic I. Anti-inflammatory, gastroprotective, and cytotoxic effects of Sideritis scardica extracts. Planta Med 2012; 78: 415-427
5 Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating. Cell Death Differ 2005; 12: 1542-1552
6 Ichimura Y, Kumanomidou T, Sou YS, Mizushima T, Ezaki J, Ueno T, Kominami E, Yamane T, Tanaka K, Komatsu M. Structural basis for sorting mechanism of p 62 in selective autophagy. J Biol Chem 2008; 83: 22847-22857
7 He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009; 43: 67-93
8 Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005; 8: 179-183
9 Wibo M, Poole B. Protein degradation in cultured cells. II. The uptake of chloroquine by rat fibroblasts and the inhibition of cellular protein degradation and cathepsin B1. J Cell Biol 1974; 63: 430-440
10 Murota K, Terao J. Antioxidative flavonoid quercetin: implication of its intestinal absorption and metabolism. Arch Biochem Biophys 2003; 417: 12-17
11 Spencer J, Mohsen M, Rice-Evans C. Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Arch Biochem Biophys 2004; 423: 148-161
12 Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2002; 2: 277-288
13 Horwitz SB. Taxol (paclitaxel): mechanisms of action. Ann Oncol 1994; 6: 3-6
14 Fliers W, Beyaert R, Declercq W, Vandenabeele P. More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene 1999; 18: 7719-7730
15 Sato F, Matsukawa Y, Matsumoto K, Nishino H, Sakai T. Apigenin induces morphological differentiation and G2-M arrest in rat neuronal cells. Biochem Biophys Res Commun 1994; 204: 578-584
16 Silva MT. Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Lett 2010; 584: 4491-4499
17 Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and selfkilling: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 2007; 8: 741-752
18 Fimia GM, Piacentini M. Toward the understanding of autophagy regulation and its interplay with cell death pathways. Cell Death Differ 2009; 16: 933-944
19 Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin I network regulates autophagy and apoptosis. Cell Death Differ 2011; 18: 571-580
20 Barth S, Glick D, Macleod K. Autophagy: assays and artifacts. J Pathol 2010; 221: 117-124
21 Huang X, Bai HM, Chen L, Li B, Lu YC. Reduced expression of LC3B-II and Beclin 1 in glioblastoma multiforme indicates a down-regulated autophagic capacity that relates to the progression of astrocytic tumors. J Clin Neurosci 2010; 17: 1515-1519
22 Tong X, Smith KA, Pellinq JC. Apigenin, a chemopreventive bioflavonoid, induces AMP-activated protein kinase activation in human keratinocytes. Mol Carcinogen 2012; 51: 268-279
23 Ruela-de-Sousa RR, Fuhler GM, Blom N, Ferreira CV, Aoyama H, Peppelenbosch MP. Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy. Cell Death Differ 2010; 1: 1-12
24 Trajković V, Badovinac V, Popadić D, Hadzić O, Stojković MM. Cell-specific effects of pentoxifylline on nitric oxide production and inducible nitric oxide synthase mRNA expression. Immunology 1997; 92: 402-406
25 Touhey S, Heenan M. Cell culture. In: Davey J, Lord JM, editors Essential cell biology. Oxford: Oxford University Press; 2003: 10-34
26 Badovinac V, Trajkovic V, Mostarica-Stojkovic M. Nitric oxide promotes growth and major histocompatibility complex-unrestricted cytotoxicity of interleukin-2-activated rat lymphocytes. Scand J Immunol 2000; 52: 62-70
27 Mijatovic S, Maksimovic-Ivanic D, Radovic J, Miljkovic D, Harhaji L, Vuckovic O, Stosic-Grujicic S, Mostarica-Stojkovic M, Trajkovic V. Anti-glioma action of aloe emodin: the role of ERK inhibition. Cell Mol Life Sci 2005; 62: 589-598