Abstract
Acetyl-boswellic acids (acetyl-BA) are pentacyclic triterpenes derived from the gum resin of frankincense. We have previously shown that these compounds are effective cytotoxic agents, acting through a mechanism that appears to involve the inhibition of topoisomerase activity. We have now investigated the mechanism of action of acetyl-BA and show that these compounds are more potent inhibitors of human topoisomerases I and IIα than camptothecin, and amsacrine or etoposide, respectively. Our data demonstrate that acetyl-BA and, to a lesser extent, some other pentacyclic triterpenes, such as betulinic acid, ursolic acid, and oleanolic acid, inhibit topoisomerases I and IIα through a mechanism that does not involve stabilization of the cleavable complex or the intercalation of DNA. Surface plasmon resonance analysis revealed that topoisomerases I and IIα bind directly to an immobilized derivative of acetyl-BA. This acetyl-BA derivative interacts with human topoisomerases through high-affinity binding sites yielding K D values of 70.6 nM for topoisomerase I and 7.6 nM for topoisomerase IIα. Based on our data, we propose that acetyl-BA inhibit topoisomerases I and IIα through competition with DNA for binding to the enzyme. Thus, acetyl-BA are a unique class of dual catalytic inhibitors of human topoisomerases I and IIα.
Footnotes
- Received November 4, 1999.
- Accepted March 7, 2000.
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Send reprint requests to: Dr. Thomas Simmet, University of Ulm, Department of Pharmacology of Natural Products and Clinical Pharmacology, Helmholtzstr. 20, D-89081 Ulm, Germany. E-mail:thomas.simmet{at}medizin.uni-ulm.de
- The American Society for Pharmacology and Experimental Therapeutics
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