TY - JOUR T1 - Acetyl-11-Keto-β-Boswellic Acid Induces Apoptosis in HL-60 and CCRF-CEM Cells and Inhibits Topoisomerase I JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 613 LP - 619 VL - 288 IS - 2 AU - R. F. Hoernlein AU - Th. Orlikowsky AU - C. Zehrer AU - D. Niethammer AU - E. R. Sailer AU - Th. Simmet AU - G. E. Dannecker AU - H. P. T. Ammon Y1 - 1999/02/01 UR - http://jpet.aspetjournals.org/content/288/2/613.abstract N2 - 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-β-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 φX174RF 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. The American Society for Pharmacology and Experimental Therapeutics ER -