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Acetyl-boswellic
acids are novel catalytic inhibitors of human topoisomerases I and IIalpha
Syrovets T,
Buchele B, Gedig E, Slupsky JR, Simmet T
Department
of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm,
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 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.
PMID:
10860928 [PubMed - indexed for MEDLINE]
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