Sulindac compounds facilitate the cytotoxicity of β-lapachone by up-regulation of NAD(P)H quinone oxidoreductase in human lung cancer cells

• Published in: PloS one 2014-02, Vol.9 (2), p.e88122
• Main Authors: Kung, Hsiu-Ni, Weng, Tsai-Yun, Liu, Yu-Lin, Lu, Kuo-Shyan, Chau, Yat-Pang
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; Adenocarcinoma - drug therapy; Adenocarcinoma - enzymology; Adenocarcinoma - genetics; Adenocarcinoma of Lung; AKT protein; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anticancer properties; Antineoplastic Agents - pharmacology; Apoptosis; Arthritis; Bark; Biology; Biotechnology; Cancer; Cancer therapies; Cell activation; Cell death; Cell Line, Tumor; Cell survival; Cytochrome; Cytotoxicity; Drug Synergism; Drugs; Enzymes; Ethanol; Humans; Inflammation; JNK protein; Laboratories; Lapachone; Lung cancer; Lung diseases; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Medicine; Metabolites; NAD; NAD(P)H Dehydrogenase (Quinone) - genetics; NAD(P)H Dehydrogenase (Quinone) - metabolism; Naphthoquinones - pharmacology; Nonsteroidal anti-inflammatory drugs; Oxidoreductase; Prostate; Quinones; Studies; Sulindac - analogs & derivatives; Sulindac - pharmacology; Toxicity; Tumor cell lines; Tumor cells; Tumors; Up-Regulation - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0088122

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.