title: Acetyl-boswellic acids are novel catalytic inhibitors of human topoisomerases I and IIalpha.
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 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 K(D) 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.
authors.affiliation: Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Syrovets
authors.forename: B
authors.initials: B
authors.lastname: Büchele
authors.forename: E
authors.initials: E
authors.lastname: Gedig
authors.forename: J R
authors.initials: JR
authors.lastname: Slupsky
authors.forename: T
authors.initials: T
authors.lastname: Simmet
mesh_terms: D000951:Antigens, Neoplasm; D001667:Binding, Competitive / Q000187:drug effects; D002384:Catalysis / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D020349:Surface Plasmon Resonance / Q000379:methods; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014315:Triterpenes; C094432:acetyl-11-ketoboswellic acid; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II