Acetyl-boswellic acids (acetyl-BA) are pentacyclic triterpenes derived from
the gum resin of frankincense. We have previously shown that these compoun
ds are effective cytotoxic agents, acting through a mechanism that appears
to involve the inhibition of topoisomerase activity. We have now investigat
ed the mechanism of action of acetyl-BA and show that these compounds are m
ore potent inhibitors of human topoisomerases I and II a than camptothecin,
and amsacrine or etoposide, respectively. Our data demonstrate that acetyl
-BA and, to a lesser extent, some other pentacyclic triterpenes, such as be
tulinic acid, ursolic acid, and oleanolic acid, inhibit topoisomer-ases I a
nd II alpha through a mechanism that does not involve stabilization of the
cleavable complex or the intercalation of DNA. Surface plasmon resonance an
alysis revealed that topoisomerases I and II alpha bind directly to an immo
bilized derivative of acetyl-BA. This acetyl-BA derivative interacts with h
uman topoisomerases through high-affinity binding sites yielding KD values
of 70.6 nM for topoisomerase I and 7.6 nM for topoisomerase II alpha. Based
on our data, we propose that acetyl-BA inhibit topoisomerases I and II alp
ha through competition with DNA for binding to the enzyme. Thus, acetyl-BA
are a unique class of dual catalytic inhibitors of human topoisomerases I a
nd II alpha.