Delphinidin modulates the DNA-damaging properties of topoisomerase II poisons.
The anthocyanidin delphinidin (DEL) has recently been shown to inhibit human topoisomerase I and II, without stabilizing the covalent DNA/topoisomerase intermediate [Habermeyer, M., Fritz, J., Barthelmes, H. U., Christensen, M. O., Larsen, M. K., Boege, F., and Marko, D. (2005) Anthocyanidins modulate the activity of human DNA topoisomerases I and II and affect cellular DNA integrity. Chem. Res. Toxicol. 18, 1395-404]. In the present study, we demonstrated that DEL affects the catalytic activity of topoisomerase IIalpha in a redox-independent manner. Furthermore, this potent inhibitory effect is not limited to a cell-free system, but is also of relevance within intact cells. DEL at micromolar concentrations was found to significantly decrease the level of topoisomerase IIalpha/DNA intermediates stabilized by the topoisomerase II poison doxorubicin in the human colon carcinoma cell line (HT29). In addition, DEL diminished the DNA-damaging properties of topoisomerase II poisons in HT29 cells without affecting the level of sites sensitive to formamidopyrimidine-DNA-glycosylase. However, the preventive effect on DNA damage exhibited an apparent maximum at a concentration of 10 microM DEL, followed by a recurrence of DNA damage at higher DEL concentrations. Furthermore, the incubation of HT29 cells with 10 microM DEL resulted in a decrease of etoposide (ETO)-induced DNA strand breaks. However, the level of ETO-stabilized covalent topoisomerase/DNA intermediates did not affect DEL, indicating an additional mechanism of action. An impact of DEL on genes involved in the repair of DNA double-strand breaks and the onset of apoptosis has to be considered. In conclusion, the natural food constituent DEL represents, depending on the concentration range, a protective factor against the DNA-damaging effects of topoisomerase II poisons in vitro. Further studies are needed to clarify whether in vivo a high DEL intake might compromise the therapeutic outcome of these anticancer agents.
Esselen
Melanie
M
Section of Food Toxicology, Institute of Applied Biosciences, Universitat Karlsruhe (TH), Adenauerring 20a, 76131 Karlsruhe, Germany.
Fritz
Jessica
J
Hutter
Melanie
M
Marko
Doris
D
D000872:Anthocyanins / Q000494:pharmacology*; D000951:Antigens, Neoplasm; D004249:DNA Damage / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000633:toxicity*; D005047:Etoposide / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000633:toxicity; D019073:HT29 Cells; D006801:Humans; D015394:Molecular Structure
D000872:Anthocyanins; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005047:Etoposide; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; C017185:delphinidin