Abstract 3519: The polyphenolic ellagitanin vescalagin is a specific inhibitor of the alpha isoform of human DNA topoisomerase II

Polyphenolic ellagitanins are natural structurally complex molecules that are often associated with the therapeutic activity of plant extracts used in traditional medicine. Studies have reported their cancer-preventing activity in animal models at concentrations found in diets. In vitro, some derivatives display cytotoxic activities at micromolar concentrations and induce apoptosis by a mechanism which remains unclear. Potential targets have been proposed, including topoisomerases (top) I and II, which are involved in the regulation of DNA topology during replication, transcription and chromosome segregation. The two human isoforms of top2: top2 alpha (top2a) and top2 beta (top2b) are the target of anticancer agents such as doxorubicin or etoposide. It is known that antitumoral activity of etoposide is primarily due the inhibition of the alpha isoform whereas inhibition of the beta isoform is primarily responsible for the development of secondary malignancies, pointing to the need for more selective top2a inhibitors. Here, we report the differential activity on top2a and top2b of new polyphenolic ellagitanins: vescalagin, methylvescalagin, acutissimin B (acuB) and epiacutissimin B (epiacuB). Using kinetoplast DNA as a substrate, we showed that top2a-mediated decatenation was strongly inhibited by all 4 derivatives at 1 µM concentration, whereas no significant inhibition of top2b could be seen. When used at 10 µM, acuB and epiacuB inhibited both isoforms and were even more active on top2b (>80% inhibition), whereas vescalagin and methylvescalagin specifically targeted top2a with a reduced effect on top2b (