Tanshinone IIA Interacts with DNA by Minor Groove-Binding

Tanshen has long been widely used as a traditional Chinese medicine. Tanshinone HA (Tan HA) is the most abundant lipophilic constituent of Tanshen which has antitumor activity but the mechanism is poorly understood. Some preliminary reports hypothesized that it is a DNA intercalator and that the furano-o-quinone moiety could produce free radicals responsible for its cytotoxicity. Here the interaction of Tan HA with DNA was explored in detail using fluorescence, viscosimetry, and molecular modeling. Tan HA was found to bind with DNA in the minor groove rather than act as an intercalator. Furthermore, the results of immunofluorescence showed that Tan HA does not produce free radicals in vivo to damage DNA. The former hypothesis was thus negated. The furan oxygen plays the key role in the antitumor ability of Tan HA because it is involved in the groove-binding, but not in the production of free radicals. The molecular basis illustrated here could be responsible for all the findings in the structure-relationship studies of tanshinone cytotoxicity.