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  1. Article: Prenylated xanthones from Metaxya rostrata suppress FoxM1 and induce active cell death by distinct mechanisms

    Mittermair, Eva / Krenn, Liselotte / Marian, Brigitte

    Phytomedicine. 2019 Apr. 01,

    2019  

    Abstract: Metaxya rostrata C.Presl (Metaxyaceae) is a tree fern widespread in Central and South America and the dried rhizome is used in ethnic medicine against intestinal ulcers or tumors. An activity-guided isolation resulted in two structurally related ... ...

    Abstract Metaxya rostrata C.Presl (Metaxyaceae) is a tree fern widespread in Central and South America and the dried rhizome is used in ethnic medicine against intestinal ulcers or tumors. An activity-guided isolation resulted in two structurally related xanthones: 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB).This study analyzed the cytotoxic activity and underlying cellular mechanisms of OH-XB for the first time in comparison to XB.We exposed the colorectal cancer cell line SW480 and F331 fibroblasts to XB and OH-XB and determined cell viability by neutral red uptake and nuclear morphology by staining with Hoechst dye. Cell cycle distribution and the mechanism of cell death were analyzed by FACS and western blot. Knockdown of FoxM1 expression was performed with siRNA.OH-XB was at least as cytotoxic as XB in the induction of cell cycle arrest and active cell death. While both compounds strongly inhibited the transcription factor FoxM1, the cellular mechanisms of growth arrest and cell death induction differed widely: OH-XB induced S-phase cell cycle arrest in contrast to a G2-M-phase arrest by XB. It caused morphological modifications typical for classical apoptosis with increased caspase 7 activity and enhanced cleavage of PARP, while XB caused caspase 2 activation and mitotic catastrophe. After knockdown of FoxM1 expression no induction of caspase activity could be observed.In summary, our data clearly showed that XB and OH-XB are promising new lead compounds for cancer therapy with distinct cellular mechanisms. Both compounds are candidates for further pre-clinical and clinical investigations.
    Keywords apoptosis ; caspases ; cell cycle checkpoints ; cell lines ; cell viability ; colorectal neoplasms ; cytotoxicity ; dyes ; enzyme activity ; fibroblasts ; intestines ; medicine ; Metaxya ; mitosis ; neoplasm cells ; rhizomes ; staining ; therapeutics ; transcription factors ; tree ferns ; Western blotting ; xanthones ; South America
    Language English
    Dates of publication 2019-0401
    Publishing place Elsevier GmbH
    Document type Article
    Note Pre-press version
    ZDB-ID 1205240-1
    ISSN 1618-095X ; 0944-7113
    ISSN (online) 1618-095X
    ISSN 0944-7113
    DOI 10.1016/j.phymed.2019.152912
    Database NAL-Catalogue (AGRICOLA)

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    Zs.A 4115: Show issues Location:
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  2. Article ; Online: Prenylated xanthones from Metaxya rostrata suppress FoxM1 and induce active cell death by distinct mechanisms.

    Mittermair, Eva / Krenn, Liselotte / Marian, Brigitte

    Phytomedicine : international journal of phytotherapy and phytopharmacology

    2019  Volume 60, Page(s) 152912

    Abstract: Background: Metaxya rostrata C.Presl (Metaxyaceae) is a tree fern widespread in Central and South America and the dried rhizome is used in ethnic medicine against intestinal ulcers or tumors. An activity-guided isolation resulted in two structurally ... ...

    Abstract Background: Metaxya rostrata C.Presl (Metaxyaceae) is a tree fern widespread in Central and South America and the dried rhizome is used in ethnic medicine against intestinal ulcers or tumors. An activity-guided isolation resulted in two structurally related xanthones: 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB).
    Hypothesis/purpose: This study analyzed the cytotoxic activity and underlying cellular mechanisms of OH-XB for the first time in comparison to XB.
    Methods: We exposed the colorectal cancer cell line SW480 and F331 fibroblasts to XB and OH-XB and determined cell viability by neutral red uptake and nuclear morphology by staining with Hoechst dye. Cell cycle distribution and the mechanism of cell death were analyzed by FACS and western blot. Knockdown of FoxM1 expression was performed with siRNA.
    Results: OH-XB was at least as cytotoxic as XB in the induction of cell cycle arrest and active cell death. While both compounds strongly inhibited the transcription factor FoxM1, the cellular mechanisms of growth arrest and cell death induction differed widely: OH-XB induced S-phase cell cycle arrest in contrast to a G2-M-phase arrest by XB. It caused morphological modifications typical for classical apoptosis with increased caspase 7 activity and enhanced cleavage of PARP, while XB caused caspase 2 activation and mitotic catastrophe. After knockdown of FoxM1 expression no induction of caspase activity could be observed.
    Conclusion: In summary, our data clearly showed that XB and OH-XB are promising new lead compounds for cancer therapy with distinct cellular mechanisms. Both compounds are candidates for further pre-clinical and clinical investigations.
    MeSH term(s) Apoptosis/drug effects ; Cell Cycle/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Death/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Colorectal Neoplasms/drug therapy ; Ferns/chemistry ; Forkhead Box Protein M1/drug effects ; Forkhead Box Protein M1/metabolism ; G2 Phase/drug effects ; Gene Knockdown Techniques ; Humans ; Mitosis/drug effects ; Prenylation ; Rhizome/chemistry ; Xanthones/chemistry ; Xanthones/pharmacology
    Chemical Substances FOXM1 protein, human ; Forkhead Box Protein M1 ; Xanthones
    Language English
    Publishing date 2019-04-02
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1205240-1
    ISSN 1618-095X ; 0944-7113
    ISSN (online) 1618-095X
    ISSN 0944-7113
    DOI 10.1016/j.phymed.2019.152912
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Destabilization of FoxM1 and Inhibition of Topoisomerase I Contribute to Cytotoxicity of Prenylated Xanthones Isolated from Metaxya rostrata.

    Mittermair, Eva / Schueffl, Hemma / Heffeter, Petra / Krenn, Liselotte / Marian, Brigitte

    Planta medica

    2020  Volume 86, Issue 15, Page(s) 1073–1079

    Abstract: We recently isolated the prenylated xanthones 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB) from the South American tree ... ...

    Abstract We recently isolated the prenylated xanthones 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB) from the South American tree fern
    MeSH term(s) Caco-2 Cells ; Cell Cycle Checkpoints ; Cell Line, Tumor ; DNA Topoisomerases, Type I ; Ferns/chemistry ; Forkhead Box Protein M1/genetics ; Humans ; Xanthones/toxicity
    Chemical Substances FOXM1 protein, human ; Forkhead Box Protein M1 ; Xanthones ; DNA Topoisomerases, Type I (EC 5.99.1.2)
    Language English
    Publishing date 2020-02-05
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 123545-x
    ISSN 1439-0221 ; 0032-0943
    ISSN (online) 1439-0221
    ISSN 0032-0943
    DOI 10.1055/a-1097-8722
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Fistula-Associated Anal Adenocarcinoma: A 20-Year Single-Center Experience.

    Harpain, Felix / Dawoud, Christopher / Wimmer, Kerstin / Schlager, Lukas / Kirchnawy, Sabine / Rizk, David / Girgis, Kerollos / Mittermair, Eva / Oberndorfer, Felicitas / Wöran, Katharina / Riss, Stefan / Stift, Anton / Stift, Judith

    Annals of surgical oncology

    2023  Volume 30, Issue 6, Page(s) 3517–3527

    Abstract: Background: Fistula-associated anal adenocarcinoma (FAAC) is a rare consequence in patients with long-standing perianal fistulas. A paucity of data are available for this patient collective, making clinical characterization and management of this ... ...

    Abstract Background: Fistula-associated anal adenocarcinoma (FAAC) is a rare consequence in patients with long-standing perianal fistulas. A paucity of data are available for this patient collective, making clinical characterization and management of this disease difficult.
    Objective: This study aimed to describe a single-center experience with FAAC patients, their clinical course, and histopathological and molecular pathological characterization.
    Methods: All patients receiving surgery for an anal fistula in 1999-2019 at a tertiary university referral hospital were included in this retrospective analysis. Patients with FAAC were eligible for histopathological analysis, including immunohistochemistry and molecular profiling.
    Results: This study included 1004 patients receiving surgical treatment for an anal fistula, of whom 242 had an underlying inflammatory bowel disease (IBD). Ten patients were diagnosed with a fistula-associated anal carcinoma (1.0%), and six of these patients had an FAAC (0.6%). The mean overall survival of FAAC patients was 24 ± 3 months. FAAC immunohistochemistry revealed positive staining for CK20, CDX2 and MUC2, while stainings for CK5/6 and CK7 were negative. All FAAC specimens revealed microsatellite stability. Molecular profiling detected mutations in 35 genes, with the most frequent mutations being TP53, NOTCH1, NOTCH3, ATM, PIK3R1 and SMAD4.
    Conclusion: FAAC is rare but associated with poor clinical outcome. Tissue acquisition is crucial for early diagnosis and therapy and should be performed in long-standing, non-healing, IBD-associated fistulas in particular. The immunophenotype of FAAC seems more similar to the rectal-type mucosa than the anal glands.
    MeSH term(s) Humans ; Retrospective Studies ; Adenocarcinoma/surgery ; Anal Canal/surgery ; Rectal Fistula/etiology ; Rectal Fistula/surgery ; Rectal Fistula/diagnosis ; Anus Neoplasms/pathology ; Inflammatory Bowel Diseases/pathology ; Treatment Outcome
    Language English
    Publishing date 2023-02-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1200469-8
    ISSN 1534-4681 ; 1068-9265
    ISSN (online) 1534-4681
    ISSN 1068-9265
    DOI 10.1245/s10434-023-13115-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4042: Show issues Location:
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  5. Article: Destabilization of FoxM1 and Inhibition of Topoisomerase I Contribute to Cytotoxicity of Prenylated Xanthones Isolated from Metaxya rostrata

    Mittermair, Eva / Schueffl, Hemma / Heffeter, Petra / Krenn, Liselotte / Marian, Brigitte

    Planta Medica

    (Special Issue Wolfgang Kubelka)

    2020  Volume 86, Issue 15, Page(s) 1073–1079

    Abstract: We recently isolated the prenylated xanthones 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB) from the South American tree fern Metaxya rostrata. This study explores the mechanisms underlying the FoxM1 downregulation ...

    Series title Special Issue Wolfgang Kubelka
    Abstract We recently isolated the prenylated xanthones 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB) from the South American tree fern Metaxya rostrata. This study explores the mechanisms underlying the FoxM1 downregulation induced by both xanthones. Analysis of cell viability and cell-death induction in SW480, HCT116, Caco-2, DLD1 and HT29 exposed to xanthones found cell-loss and activation of caspase in all cell lines except HT29 that do not have high FoxM1 protein levels. To determine the cellular mechanism of xanthone-induced FoxM1 loss, protein stability was analyzed by cycloheximide-chase experiments and showed reduction of FoxM1 stability by XB but not OH-XB. Destabilization was prevented by inhibiting proteasome activity using MG-132 and moderately by the lysosomal inhibitor bafilomycin A1 (baf A1). OH-XB had a stronger impact than XB on FoxM1 mRNA expression by qRT-PCR, and MG-132 positively affected FoxM1 protein level in

    OH-XB exposed cells even though no decrease in protein abundance had been induced by the xanthone. Additionally, the compound inhibited topoisomerase I causing DNA DSB and early cell cycle arrest. This may reduce FoxM1 gene expression, which may in turn compromise DNA repair and enhance xanthone-induced cell death. With regard to xanthone-induced cell death, MG-132 protected cultures from cell loss induced by both compounds, and baf A1 was active against these XB-induced effects. In summary, both destabilization of FoxM1 protein and topoisomerase I inhibition contribute to both XB and OH-XB cytotoxic activity albeit at different ratios.
    Keywords 2-deprenyl-rheediaxanthone B, 2-deprenyl-7-hydroxy-rheediaxanthone B, ; Metaxyaceae ; FoxM1 ; topoisomerase I
    Language English
    Publishing date 2020-02-05
    Publisher Georg Thieme Verlag KG
    Publishing place Stuttgart ; New York
    Document type Article
    ZDB-ID 123545-x
    ISSN 1439-0221 ; 0032-0943
    ISSN (online) 1439-0221
    ISSN 0032-0943
    DOI 10.1055/a-1097-8722
    Database Thieme publisher's database

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  6. Article ; Online: Flavonoids Distinctly Stabilize Lymph Endothelial- or Blood Endothelial Disintegration Induced by Colon Cancer Spheroids SW620.

    Berenda, Julia / Smöch, Claudia / Stadlbauer, Christa / Mittermair, Eva / Taxauer, Karin / Huttary, Nicole / Krupitza, Georg / Krenn, Liselotte

    Molecules (Basel, Switzerland)

    2020  Volume 25, Issue 9

    Abstract: The health effects of plant phenolics in vegetables and other food and the increasing evidence of the preventive potential of flavonoids in "Western Diseases" such as cancer, neurodegenerative diseases and others, have gained enormous interest. This ... ...

    Abstract The health effects of plant phenolics in vegetables and other food and the increasing evidence of the preventive potential of flavonoids in "Western Diseases" such as cancer, neurodegenerative diseases and others, have gained enormous interest. This prompted us to investigate the effects of 20 different flavonoids of the groups of flavones, flavonols and flavanones in 3D in vitro systems to determine their ability to inhibit the formation of circular chemorepellent induced defects (CCIDs) in monolayers of lymph- or blood-endothelial cells (LECs, BECs; respectively) by 12(S)-HETE, which is secreted by SW620 colon cancer spheroids. Several compounds reduced the spheroid-induced defects of the endothelial barriers. In the SW620/LEC model, apigenin and luteolin were most active and acacetin, nepetin, wogonin, pinocembrin, chrysin and hispidulin showed weak effects. In the SW620/BEC model acacetin, apigenin, luteolin, wogonin, hispidulin and chrysin exhibited weak activity.
    MeSH term(s) Antineoplastic Agents, Phytogenic/chemistry ; Antineoplastic Agents, Phytogenic/pharmacology ; Coculture Techniques ; Colonic Neoplasms/metabolism ; Colonic Neoplasms/pathology ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/metabolism ; Flavonoids/chemistry ; Flavonoids/pharmacology ; Humans ; Neovascularization, Pathologic/metabolism ; Spheroids, Cellular
    Chemical Substances Antineoplastic Agents, Phytogenic ; Flavonoids
    Language English
    Publishing date 2020-04-29
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules25092066
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 81: Show issues

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  7. Article ; Online: Methylated Xanthones from the Rootlets of

    Mittermair, Eva / Kählig, Hanspeter / Tahir, Ammar / Rindler, Stefanie / Hudec, Xenia / Schueffl, Hemma / Heffeter, Petra / Marian, Brigitte / Krenn, Liselotte

    Molecules (Basel, Switzerland)

    2020  Volume 25, Issue 19

    Abstract: ... The tree ... ...

    Abstract The tree fern
    MeSH term(s) Carbon-13 Magnetic Resonance Spectroscopy ; Caspases/metabolism ; Cell Cycle Proteins/metabolism ; Cell Death/drug effects ; Cell Line, Tumor ; Colorectal Neoplasms/pathology ; DNA Topoisomerases, Type I/metabolism ; Ferns/chemistry ; Humans ; Methylation ; Plant Roots/chemistry ; Proton Magnetic Resonance Spectroscopy ; Topoisomerase Inhibitors/pharmacology ; Xanthones/chemistry ; Xanthones/pharmacology
    Chemical Substances Cell Cycle Proteins ; Topoisomerase Inhibitors ; Xanthones ; Caspases (EC 3.4.22.-) ; DNA Topoisomerases, Type I (EC 5.99.1.2)
    Language English
    Publishing date 2020-09-28
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 1413402-0
    ISSN 1420-3049 ; 1431-5165 ; 1420-3049
    ISSN (online) 1420-3049
    ISSN 1431-5165 ; 1420-3049
    DOI 10.3390/molecules25194449
    Database MEDical Literature Analysis and Retrieval System OnLINE

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