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    Bioactivity-guided isolation of cytotoxic secondary metabolites from the roots of Glycyrrhiza glabra and elucidation of their mechanisms of action
    (ELSEVIER SCIENCE BV, 2018) Cevik, Dicle; Yilmazgoz, S. Burcin; Kan, Yuksel; Guzelcan, Ece Akhan; Durmaz, Irem; Cetin-Atalay, Rengul; Kirmizibekmez, Hasan
    Licorice (Glycyrrhiza glabra L.) is one of the most widely used plants worldwide for its various pharmacological activities. The aim of this study was to isolate the potential cytotoxic secondary metabolites from the MeOH extract prepared from the roots of Glycyrrhiza glabra through bioactivity-guided isolation procedure and to elucidate their mechanisms of action. The crude MeOH extract as well as CHCl3 and EtOAc subextracts significantly inhibited cell proliferation on hepatocelullar (Huh7), breast (MCF7) and colorectal (HCT116) cancer cell lines with IC50 values in the range of 5.6 to 33.6 mu g/mL. Chromatographic seperations of the CHCl3 and EtOAc subextracts yielded 13 secondary metabolites. Structures were characterized based on NMR and MS data. Amongst isolates, glabridin (1), 4'-O-methylglabridin (2), beta-amyrin (3), kanzonol U (4), glabrene (7) and tet-rahydroxymethoxychalcone (10) were established to be responsible for in vitro cytotoxicity of G. glabra, exerting the best activity particularly against Huh7 cells. Further mechanistic studies demonstrated that 2 and 7 induced caspase-dependent apoptosis by increasing cytochrome C release and subsequently cleaved caspase-9 level in Huh7 cells. Moreover, both compounds decreased pRb and p21 levels and thus induced the accumulation of Huh-7 cells in subG(1) and G(2)/M phases. Compound 10 which displayed the most potent activity in Hoechst staining and cell cycle assays through G(2)/M arrest, caused cell death by apoptosis in Huh7 cells.
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    Mechanisms of action of cytotoxic phenolic compounds from Glycyrrhiza iconica roots
    (ELSEVIER GMBH, 2019) Cevik, Dicle; Kan, Yuksel; Kirmizibekmez, Hasan
    Background: Glycyrrhiza (licorice) species are rich in bioactive secondary metabolites and their roots are used traditionally for the treatment of several diseases. In recent years, secondary metabolites of licorice are gaining popularity, especially due to their significant cytotoxic and antitumor effects. However, Glycyrrhiza iconica, an endemic species to Turkey, was not investigated in terms of its anticancer secondary metabolites previously. Purpose: This study aimed to isolate the cytotoxic compounds from G. iconica through bioactivity-guided fractionation and to elucidate mechanisms of action of the most potent compounds. Methods: Total MeOH extract and CHCl3, EtOAc, n-buOH and rH(2)O subextracts were prepared from G. iconica roots. Sequential chromatographic techniques were conducted for the isolation studies. The chemical structures of the isolates were established based on NMR and HR-MS analysis. Sulforhodamine B assay was used to evaluate the cytotoxic activity of extracts, main fractions as well as isolates against hepatocellular (Huh7), breast (MCF7) and colorectal (HCT116) cancer cell lines. The mechanisms underlying the cytotoxicity of the most active compounds in Huh7 cells were elucidated by using Hoechst staining, Fluorescence-activated cell sorting and Western blot assays. Results: A new dihydrochalcone, iconichalcone (1) along with 15 known phenolic compounds were isolated from the active CHCl3, EtOAc and n-buOH subextracts. Compounds 2-5, 7-16 were found to be responsible for the in vitro cytotoxic activity of G. iconica against all tested cancer cell lines with IC50 values ranging from 2.4 to 33 mu M. Amongst these compounds, licoricidin (10), dehydroglyasperin C (12), iconisoflaven (13) and 1-methoxyficifolinol (15) were found to be the most active compounds according to SRB and real time bioactivity assays and submitted to further mechanistic investigations in Huh7 cells. Compounds 10, 12, 13 and 15 caused accumulation of cells in different phases of cell cycle. Moreover, 10, 12, 13 and 15 induced apoptosis through caspase activation. Besides, 12 showed activation of p53 expression and thus G(2)/M arrest as well as a condensed nuclei, established very promising results. Conclusion: The results demonstrated that the aforementioned compounds, particularly 12 could be potential lead molecules for anticancer drug development that deserve further in vivo and clinical investigations.