Synergistic effect of ionizing radiation and beta-lapachone against cancer cells

초록

β-laphachone (β-Lap), a natural o-naphthoquinone, presents in the bark of the Lapacho tree. β-Lap is cytotoxic against a variety of human cancer cells and it potentiates the anti-tumor effect of Taxol. In addition, β-Lap has been reported to radiosensitize cancer cells by inhibiting the repair of radiation-induced DNA damage. In the present study, we investigated the cytotoxicity of β-Lap against RKO human colorectal cancer cells as well as the combined effect of β-Lap and ionizing radiation. An incubation of RKO cells with 5 uM of β-Lap for 4 h killed almost 90% of the clonogenic cells. An incubation of RKO cells with 5 uM of β-Lap for 4 h or longer also caused massive apoptosis. Unlike other cytotoxic agents, β-Lap did not increase the expression of p53 and p21and it suppressed the NFkβ expression. The expression of Caspase 9 and 3 was minimally altered by β-Lap. Radiation and β-Lap acted synergistically in inducing clonogenic cell death and apoptosis in RKO cells when β-Lap treatment was applied after but not before the radiation exposure of the cells. Interestingly, a 4 h treatment with 5 uM of β-Lap starting 5 h after irradiation was as effective as that starting immediately after irradiation. The mechanisms of β-Lap-induced cell killing is controversial but a recent hypothesis is that β-Lap is activated by NAD(P)H:quinone-oxidoreductase (NQO1) in the cells followed by an elevation of cytosolic Ca2+ level and activation of proteases leading to apoptosis.