| Summary: | 碩士 === 國立陽明大學 === 解剖學及細胞生物學研究所 === 98 === Lung cancer is common and the most cause of cancer death in Taiwan. β-Lapachone (β-lap), a novel bio-oxidoreductive drug, exhibits cytotoxic to cancer cells expressing the NADP(H): quinone oxidoreductase-1(NQO1). NQO1 is an important enzyme that reduces quinones to hydroquinones for preventing the generation of the semiquinone radical. Sulindac and its metabolites, sulindac sulfide and sulindac sulfone, are non-steroidal anti-inflammatory drugs and may increase the protein expression and enzyme activity of NQO1.
In this study, we compared the NQO1 protein levels and NQO1 activities of A549, CL1-1, and CL1-5 cells, respectively. The NQO1 expression and activity in A549 is high, CL1-1 is moderate and CL1-5 is weak. From experimental results, we demonstrated that (1) the treatment of sulindac, sulindac sulfide and sulindac sulfone significantly upregulates the NQO1 expression and NQO1 activity in lung cancer cells ; (2) The combination of sulindac or sulindac derivates and β-lapachone has synergistic cytotoxic effects on lung cancer cell lines and (3) Counteracting NQO1 activity with NQO1 inhibitor, dicumoral or decreasing NQO1 mRNA and protein levels with NQO1 siRNA significantly prevented the cell death induced by the combination of NSAIDs and β-lapachone. In conclusion, this study suggests that the treatment with the combination of β-lapachone and sulindac or sulindac derivates (sulindac sulfide or sulindac sulfone) may enhance the cytotoxic effect of β-lapachone and provide an effective chemotherapy for lung cancer.
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