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.
Key words
2-deprenyl-rheediaxanthone B, 2-deprenyl-7-hydroxy-rheediaxanthone B,
Metaxya rostrata
- Metaxyaceae - FoxM1 - topoisomerase I
