Cudraflavanone A purified from Cudrania tricuspidata induces apoptotic cell death of human leukemia U937 cells, at least in part, through the inhibition of DNA topoisomerase I and protein kinase C activity

Abstract

A chloroform extract of the root bark of Cudrania tricuspidata showed an inhibitory effect on mammalian DNA topoisomerase I. The topoisomerase I inhibitory compound was purified and identified as 2S-2',5,7-trihydroxy-4',5'-(2,2-dimethylchromeno)-6-prenyl flavanone (cudraflavanone A). Cudraflavanone A was shown to inhibit the activity of topoisomerase I with approximately 0.4 mmol/l 50% inhibitory concentration. A concentration of 6 micromol/l cudraflavanone A caused a 50% growth inhibition of human cancer cell U937. Cudraflavanone A-induced cell death was characterized by the cleavage of poly(ADP-ribose) polymerase and pro-caspase-3. Furthermore, cudraflavanone A induced the fragmentation of DNA into multiples of 180 bp (an apoptotic DNA ladder), indicating that the inhibitor triggered apoptosis. This induction of apoptosis by cudraflavanone A was also confirmed using flow-cytometry analysis. In addition, this compound inhibited protein kinase C activity with approximately 150 micromol/l 50% inhibitory concentration. Taken together, these results suggest that cudraflavanone A may function by inhibiting oncogenic disease, at least in part, through the inhibition of protein kinase C and topoisomerase I activity.