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Vol. 58, Issue 1, 71-81, July 2000

Acetyl-Boswellic Acids Are Novel Catalytic Inhibitors of Human Topoisomerases I and IIalpha

Tatiana Syrovets, Berthold Büchele, Erk Gedig, Joseph R. Slupsky, and Thomas Simmet

Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm (Ta.S., B.B., W.Z., J.R.S., Th.S); and XanTec Analysensysteme, Muenster (E.G.), Germany

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 IIalpha 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 IIalpha 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 IIalpha bind directly to an immobilized derivative of acetyl-BA. This acetyl-BA derivative interacts with human topoisomerases through high-affinity binding sites yielding KD values of 70.6 nM for topoisomerase I and 7.6 nM for topoisomerase IIalpha . Based on our data, we propose that acetyl-BA inhibit topoisomerases I and IIalpha 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 IIalpha .

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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