RT Journal Article
SR Electronic
T1 Acetyl-Boswellic Acids Are Novel Catalytic Inhibitors of Human Topoisomerases I and IIα
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 71
OP 81
DO 10.1124/mol.58.1.71
VO 58
IS 1
A1 Tatiana Syrovets
A1 Berthold Büchele
A1 Erk Gedig
A1 Joseph R. Slupsky
A1 Thomas Simmet
YR 2000
UL http://molpharm.aspetjournals.org/content/58/1/71.abstract
AB 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.