Association between Expression of NAD(P)H: Quinone Oxidoreductase 1 (NQO1) and Synergistic Effect of Ionizing Radiation and beta-lapachone on Human Lung Cancer Cell Line (A549)

ABSTRACT

PURPOSE: beta-lapachone ( beta-lap) has cytotoxic effect in a number of human cancer cell lines and through a unuique apoptotic pathway that is dependent upon NQO1, a two-electron reductase. beta-lap was an effective agent alone, and in conbination with radiation or taxol with low-level host toxicity. We investigated the cytotoxicity of beta-lap against A459 human lung cancer cells as well as the combined effect of beta-lap and ionizing radiation. MATERIALS AND METHODS: An incubation of A459, HN3 and HN9 cells with 5 M of beta-lap for 4 h killed almost 90% of the clonogenic cells. Raidation and beta-lap acted synergistically in including clonogenic cell death and apoptosis in A549 cells when beta-lap treatment was applied after but not before the radiation exposure of the cells. Interestingly, a 4 h treatment with 5 M of beta-lap starting 5 h after irradiation was as effective as that stating immediately after irradiation. The mechanisms of beta-lap induced cell killing is supposed that beta-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. RESULTS: We observed that beta-lap killed human lung and head neck cancer cells by an apoptotic response significantly enhanced by NAD(P)H quinone oxidoreductase (NQO1) enzymatic activity after 4 Gy irradiation. CONCLUSION: Taken together, we may conclude that the synergistic interaction of radiation and beta-lap in killing cancer cells is not due to radiosensitization by beta-lap but to enhancement of beta-lap cytotoxocity by radiation through upregulation of NQO1