Prenylated xanthones from Metaxya rostrata suppress FoxM1 and induce active cell death by distinct mechanisms

Mittermair, Eva; Krenn, Liselotte; Marian, Brigitte

doi:10.1016/j.phymed.2019.152912

Cited by 7 publications

(26 citation statements)

References 25 publications

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“…They show that the xanthones were effective in the same concentration range as IRI but about 1000-fold less than the activated metabolite SN-38. OH-XB was more effective than XB for SW480 as reported before [7] and for HCT116 cells, while Caco-2 and DLD1 cells were more sensitive to XB than to OH-XB. No IC 50 could be determined for DLD1 because the cytotoxic effect leveled out at > 50 %.…”

Section: Resultssupporting

confidence: 78%

“…2 c). Also, caspase activity was higher for OH-XB than XB in SW480 [7] and in HCT116 cells, while it was similar for both xanthones in Caco2 and DLD1 cultures (▶ Fig. 2…”

Section: Resultsmentioning

confidence: 91%

“…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%

“…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%

“…XB and the closely related compound OH-XB both downregulate the growth-associated transcription factor FoxM1 and induce cell death in CRC cells. However, they also act via distinct cellular mechanisms as shown by the differences in cell cycle arrest and caspase activation [7]. This current study aimed to characterize the exact mode of interaction between the prenylated xanthones Supporting information available online at http://www.thieme-connect.de/products…”

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: Resultssupporting

confidence: 78%

“…2 c). Also, caspase activity was higher for OH-XB than XB in SW480 [7] and in HCT116 cells, while it was similar for both xanthones in Caco2 and DLD1 cultures (▶ Fig. 2…”

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Self Cite

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Retracted: MicroRNA‐4429 restrains colorectal cancer cell invasion and migration via regulating SMAD3‐induced epithelial–mesenchymal transition

Liang

Zhang

et al. 2021

Journal Cellular Physiology

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Colorectal cancer (CRC) is one of the commonest human cancers and the fourth primary cause of cancer‐related death. Previous studies have reported that miR‐4429 develops anticancer function in follicular thyroid carcinoma and non‐small cell lung cancer. However, whether miR‐4429 is implicated in the CRC progression remains to be clarified. The aim of our current study was to explore the potential role of miR‐4429 in CRC. According to the result of quantitative real‐time polymerase chain reaction analysis, miR‐4429 was expressed at a low level in CRC cells. Gain‐of‐function assays showed that the upregulation of miR‐4429 inhibited cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) process in CRC, whereas miR‐4429 inhibition led to the opposite results. It was uncovered from mechanism experiments that miR‐4429 targeted forkhead box M1 (FOXM1) and therefore regulating SMAD family member 3 (SMAD3) expression. Rescue experiments elucidated that miR‐4429 influenced cell proliferation, migration, invasion, and EMT process in CRC by targeting FOXM1 to inactivate SMAD3. In conclusion, our study revealed that miR‐4429 targeted FOXM1 to decrease SMAD3 expression and thus impeding cell proliferation, migration, invasion, and EMT process of CRC cells.

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The mechanisms of action of prenylated xanthones against breast, colon, and lung cancers, and their potential application against drug resistance

et al. 2022

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Prenylated xanthones from Metaxya rostrata suppress FoxM1 and induce active cell death by distinct mechanisms

Cited by 7 publications

References 25 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

Retracted: MicroRNA‐4429 restrains colorectal cancer cell invasion and migration via regulating SMAD3‐induced epithelial–mesenchymal transition

The mechanisms of action of prenylated xanthones against breast, colon, and lung cancers, and their potential application against drug resistance

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