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Vol. 288, Issue 2, 613-619, February 1999
-Boswellic Acid Induces Apoptosis in HL-60 and
CCRF-CEM Cells and Inhibits Topoisomerase I
Institute of Pharmaceutical Sciences, Department of Pharmacology,
Tuebingen, Germany (R.F.H., E.R.S., H.P.T.A.);
Children's University
Hospital, Department of Haematology, Tuebingen, Germany (T.O., C.Z.,
D.N., G.E.D.); and
Department of Pharmacology and Toxicology, Ruhr
University, Bochum, Germany (T.S.)
Antiproliferative action of different pentacyclic triterpenes has
repeatedly been reported, and some lipoxygenase inhibitors have been
shown to induce cell death in various cell systems. Acetyl-11-keto-
-boswellic acid (AKBA) is a pentacyclic triterpene that inhibits 5-lipoxygenase in a selective, enzymedirected,
nonredox, and noncompetitive manner. To investigate a possible effect
of AKBA on leukemic cell growth, proliferation of HL-60 and CCRF-CEM cells was assayed in the presence of AKBA and a structural analog without effect on 5-lipoxygenase, amyrin. Cell counts and
[3H]thymidine incorporation were significantly reduced in
a dose-dependent manner in the presence of AKBA (IC50 = 30 µM) but not amyrin. An additive effect of AKBA with the crosslinking
of the CD95 receptor was also observed. Flow cytometric analysis of
propidium iodide-stained cells indicated that the cells underwent
apoptosis. This was confirmed by flow cytometric detection of
sub-G1 peaks in AKBA-treated cells and by DNA laddering.
However, because HL-60 and CCRF-CEM do not express 5-lipoxygenase mRNA
constitutively, a mechanism distinct from inhibition of 5-lipoxygenase
must account for the effect of AKBA. In a DNA relaxation assay with
X174RF DNA, AKBA inhibited topoisomerase I from calf thymus
at concentrations of 
10 µM. A semiquantitative cDNA polymerase
chain reaction approach was used to estimate the relative level of
expression of topoisomerases in both cell lines. The data suggest that
induction of apoptosis in HL-60 and CCRF-CEM by AKBA may be due to
inhibition of topoisomerase I in these cells.
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