Abstract
β-lapachone, a major component in an ethanol extract of Tabebuia avellanedae bark, is a promising potential therapeutic drug for various tumors, including lung cancer, the leading cause of cancer-related deaths worldwide. In the first part of this study, we found that apoptotic cell death induced in lung cancer cells by high concentrations of β-lapachone was mediated by increased activation of the pro-apoptotic factor JNK and decreased activation of the cell survival/proliferation factors PI3K, AKT, and ERK. In addition, β-lapachone toxicity was positively correlated with the expression and activity of NAD(P)H quinone oxidoreductase 1 (NQO1) in the tumor cells. In the second part, we found that the FDA-approved non-steroidal anti-inflammatory drug sulindac and its metabolites, sulindac sulfide and sulindac sulfone, increased NQO1 expression and activity in the lung adenocarcinoma cell lines CL1-1 and CL1-5, which have lower NQO1 levels and lower sensitivity to β-lapachone treatment than the A549 cell lines, and that inhibition of NQO1 by either dicoumarol treatment or NQO1 siRNA knockdown inhibited this sulindac-induced increase in β-lapachone cytotoxicity. In conclusion, sulindac and its metabolites synergistically increase the anticancer effects of β-lapachone primarily by increasing NQO1 activity and expression, and these two drugs may provide a novel combination therapy for lung cancers.
Highlights
Introduction bLapachone, a natural o-naphthoquinone originally obtained from lapacho trees in South America, has promising anti-tumor activity on various tumor cells [1,2,3,4,5,6] and has been tested as an antitumor candidate drug in phase I/II/III clinical trials in combination with other chemotherapy drugs [1,7]
NAD(P)H quinone oxidoreductase 1 (NQO1) Expression and Activity in Lung Cancer Cells Correlate with b-lapachone Toxicity
Since NQO1 activity has been positively correlated with b-lapachone cytotoxicity in breast cancer cell lines [8,9,44], we examined whether the sensitivity of the different lung cancer cell lines to b-lapachone toxicity was associated with intracellular NQO1 expression
Summary
Introduction bLapachone, a natural o-naphthoquinone originally obtained from lapacho trees in South America, has promising anti-tumor activity on various tumor cells [1,2,3,4,5,6] and has been tested as an antitumor candidate drug in phase I/II/III clinical trials in combination with other chemotherapy drugs [1,7]. We used lower concentrations of b-lapachone to explore whether sulindac and its metabolites could facilitate the anticancer effect of b-lapachone by increasing NQO1 expression or activity in lung cancer cell lines with low NQO1 levels and checked the importance of NQO1 in this combination therapy.
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