Sulindac compounds facilitate the cytotoxicity of β-lapachone by up-regulation of NAD(P)H quinone oxidoreductase in human lung cancer cells
Journal
PLoS ONE
Journal Volume
9
Journal Issue
2
Pages
e88122
Date Issued
2014
Author(s)
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. ? 2014 Kung et al.
SDGs
Other Subjects
beta lapachone; mitogen activated protein kinase; phosphatidylinositol 3 kinase; protein kinase B; reduced nicotinamide adenine dinucleotide (phosphate) dehydrogenase (quinone); stress activated protein kinase; sulindac; sulindac sulfide; sulindac sulfone; antineoplastic activity; apoptosis; article; cancer cell culture; cancer resistance; cell proliferation; cell survival; concentration response; controlled study; down regulation; drug cytotoxicity; drug potentiation; drug sensitivity; drug targeting; enzyme activation; enzyme regulation; human; human cell; lung adenocarcinoma; lung cancer; protein expression; signal transduction; upregulation; Adenocarcinoma; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Cell Line, Tumor; Drug Synergism; Humans; Lung Neoplasms; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Sulindac; Up-Regulation
Publisher
Public Library of Science
Type
journal article