Synergistic Effect of Ionising Radiation and β-lapachone against Tumor in vitro and in vivo

초록

Bacgorund: β-lapachone(β-Lap) cytotoxic against a variety of human cancer cells and β-Lap has been reported to radiosensitixe cancer cells, We investigated the cytotoxicity of β-Lap against RKO human colorectal cancer cells as well as the combined effect of β-Lap and ionixing radiation. Methods: An incubation of RKO cells with 5μM of β-Lap for 4 h killed almost 90% of the clonogenic cells, Unlike other cytotoxic agents, β-Lap did not increase the expression of p53 and p21 and it suppressed the NFkβ expression. Raidation and β-Lap acted synergistically in including 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 5μM of β-Lap starting 5h after irradiation was as effective as that stating immediately after irradiation. The mechanisms of β-Lap induced cell killing is supposed that β-Lap is activated by NAPD(P)H: quinone-oxdoreductase (NQO1) in the cells followed by an elevation of cytoslic Ca2+ level and activation of proteases leading to apoptosis. Results: We observed a significant elevation of NQO1 expression in RKO cells 5h after 2~4 Gy irradiation. For in vivo study, RKO cells were injected S.C. into the hind-leg of Nu/Nu mice. The mice were i.p. injected with β-Lap of saline 2 h after irradiation of tumors with 10 Gy of X-ray. The radiation induced growh delay was increased by 2.4μg/g of β-Lap . Conclusion: Taken together, we may conclude tht the synergisic interaction of radiation and β-Lap in killing cacer cells is not due to radiosensitization by β-Lap but to enhancement of β-Lap cytotoxocity by radiation through upregulation of NQO1.