Inhibition of DNA Topoisomerase I by Dihydrotanshinone I, Components of a Medicinal Herb<i>Salvia miltiorrhiza</i>Bunge

Abstract

Dihydrotanshinone I induced topoisomerase I-mediated DNA cleavage in vitro as strongly as camptothecin, but topoisomerase II-mediated DNA cleavage was not affected. In a DNA relaxation assay using calf thymus DNA topoisomerase I and supercoiled pBR322 plasmid DNA, dihydrotanshinone I reduced topoisomerase I-mediated DNA relaxation in a dose-dependent manner. Heat treatment (65°C) of the reaction mixture containing dihydrotanshinone I and topoisomerase I resulted in a substantial reduction in DNA cleavage, suggesting topoisomerase I and dihydrotanshinone I may form a reversible cleavable complex to induce DNA damage. A DNA unwinding assay using T4 DNA ligase showed that dihydrotanshinone I is a very weak DNA intercalator. These results suggest that dihydrotanshinone I inhibits the catalytic activity of topoisomerase I by the formation of a cleavable complex and at least in part through the intercalation into DNA.