Details

Autor(en) / Beteiligte

• Habermeyer, Michael
• Fritz, Jessica
• Barthelmes, Hans U
• Christensen, Morten O
• Larsen, Morten K
• Boege, Fritz
• Marko, Doris

Titel

Anthocyanidins Modulate the Activity of Human DNA Topoisomerases I and II and Affect Cellular DNA Integrity

Ist Teil von

• Chemical research in toxicology, 2005-09, Vol.18 (9), p.1395-1404

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2005

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• In the present study, we investigated the effect of anthocyanidins on human topoisomerases I and II and its relevance for DNA integrity within human cells. Anthocyanidins bearing vicinal hydroxy groups at the B-ring (delphinidin, DEL; cyanidin, CY) were found to potently inhibit the catalytic activity of human topoisomerases I and II, without discriminating between the IIα and the IIβ isoforms. However, in contrast to topoisomerase poisons, DEL and CY did not stabilize the covalent DNA-topoisomerase intermediates (cleavable complex) of topoisomerase I or II. Using recombinant topoisomerase I, the presence of CY or DEL (≥1 μM) effectively prohibited the stabilization of the cleavable complex by the topoisomerase I poison camptothecin. We furthermore investigated whether the potential protective effect vs topoisomerase I poisons is reflected also on the cellular level, affecting the DNA damaging properties of camptothecin. Indeed, in HT29 cells, low micromolar concentrations of DEL (1−10 μM) significantly diminished the DNA strand breaking effect of camptothecin (100 μM). However, at concentrations ≥50 μM, all anthocyanidins tested (delphinidin, cyanidin, malvidin, pelargonidin, and paeonidin), including those not interfering with topoisomerases, were found to induce DNA strand breaks in the comet assay. All of these analogues were able to compete with ethidium bromide for the intercalation into calf thymus DNA and to replace the minor groove binder Hoechst 33258. These data indicate substantial affinity to double-stranded DNA, which might contribute at least to the DNA strand breaking effect of anthocyanidins at higher concentrations (≥50 μM).