2-Deprenyl-Rheediaxanthone B Isolated from Metaxya rostrata Induces Active Cell Death in Colorectal Tumor Cells

Kainz, Kerstin P.; Krenn, Liselotte; Erdem, Zeynep; Kaehlig, Hanspeter; Zehl, Martin; Bursch, Wilfried; Berger, Walter; Marian, Brigitte

doi:10.1371/journal.pone.0065745

Cited by 10 publications

(26 citation statements)

References 41 publications

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“…In addition, caspase activity was measured for HCT116, Caco-2, HT29, and DLD1 cells by a standard enzyme assay with the substrate Ac-DEVD-APC [7]. For the SW480 cell line, which had shown highest sensitivity to XB and OH-XB in our previous studies [7,8], caspase activity was increased by exposure to 15 µM XB or OH-XB 1.5-fold and 3-fold respectively [7]. The same concentration of IRI activated caspase about 4-fold ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, experiments to explore xanthone effects on FoxM1 protein were initiated and were done using SW480 cells because this cell line had demonstrated the highest sensitivity to both xanthones (▶ Fig. 2 a and [7,8]). Furthermore, our previous results had described a strong suppression of FoxM1 by both compounds in this cell line after 48 h [7].…”

Section: C)mentioning

confidence: 99%

“…XB and OH-XB were isolated from the rootlets of Metaxya rostrata with a proven purity as reported [7,8]. Cyc (#128M4081V), MG-132 (#098M4000V), and baf A1 (#068M4088V) were obtained from SIGMA-ALDRICH Chemie GmbH.…”

Section: Compoundsmentioning

confidence: 99%

“…We recently isolated and characterized prenylated xanthones from Metaxya rostrata (Kunth) C. Presl (Metaxyaceae), a tree fern from the rainforests of Central and South America [7,8]. XB and the closely related compound OH-XB both downregulate the growth-associated transcription factor FoxM1 and induce cell death in CRC cells.…”

Section: Introductionmentioning

confidence: 99%

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Destabilization of FoxM1 and Inhibition of Topoisomerase I Contribute to Cytotoxicity of Prenylated Xanthones Isolated from Metaxya rostrata

Mittermair

Schueffl²,

Heffeter³

et al. 2020

Planta Med

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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.

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Section: Resultsmentioning

confidence: 99%

Section: C)mentioning

confidence: 99%

Section: Compoundsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Destabilization of FoxM1 and Inhibition of Topoisomerase I Contribute to Cytotoxicity of Prenylated Xanthones Isolated from Metaxya rostrata

Mittermair

Schueffl²,

Heffeter³

et al. 2020

Planta Med

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“…Nuclei were isolated and stained with PI as described before [17], [18]. Samples were measured with FACSCalibur (BD).…”

Section: Methodsmentioning

confidence: 99%

Irinotecan Upregulates Fibroblast Growth Factor Receptor 3 Expression in Colorectal Cancer Cells, Which Mitigates Irinotecan-Induced Apoptosis

Erdem

Schwarz

Drev

et al. 2017

Translational Oncology

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BACKGROUND: Irinotecan (IRI) is an integral part of colorectal cancer (CRC) therapy, but response rates are unsatisfactory and resistance mechanisms are still insufficiently understood. As fibroblast growth factor receptor 3 (FGFR3) mediates essential survival signals in CRC, it is a candidate gene for causing intrinsic resistance to IRI. METHODS: We have used cell line models overexpressing FGFR3 to study the receptor's impact on IRI response. For pathway blockade, a dominant-negative receptor mutant and a small molecule kinase inhibitor were employed. RESULTS: IRI exposure induced expression of FGFR3 as well as its ligands FGF8 and FGF18 both in cell cultures and in xenograft tumors. As overexpression of FGFR3 mitigated IRI-induced apoptosis in CRC cell models, this suggests that the drug itself activated a survival response. On the cellular level, the antiapoptotic protein bcl-xl was upregulated and caspase 3 activation was inhibited. Targeting FGFR3 signaling using a dominant-negative receptor mutant sensitized cells for IRI. In addition, the FGFR inhibitor PD173074 acted synergistically with the chemotherapeutic drug and significantly enhanced IRI-induced caspase 3 activity in vitro. In vivo, PD173074 strongly inhibited growth of IRI-treated tumors. CONCLUSION: Together, our results indicate that targeting FGFR3 can be a promising strategy to enhance IRI response in CRC patients.

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Xanthones and biphenyls from the stems of Garcinia cylindrocarpa and their cytotoxicity

et al. 2018

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2-Deprenyl-Rheediaxanthone B Isolated from Metaxya rostrata Induces Active Cell Death in Colorectal Tumor Cells

Cited by 10 publications

References 41 publications

Destabilization of FoxM1 and Inhibition of Topoisomerase I Contribute to Cytotoxicity of Prenylated Xanthones Isolated from Metaxya rostrata

Destabilization of FoxM1 and Inhibition of Topoisomerase I Contribute to Cytotoxicity of Prenylated Xanthones Isolated from Metaxya rostrata

Irinotecan Upregulates Fibroblast Growth Factor Receptor 3 Expression in Colorectal Cancer Cells, Which Mitigates Irinotecan-Induced Apoptosis

Xanthones and biphenyls from the stems of Garcinia cylindrocarpa and their cytotoxicity

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