Triptolide reverses the Taxol resistance of lung adenocarcinoma by inhibiting the NF-kappa B signaling pathway and the expression of NF-kappa B-regulated drug-resistant genes

摘要

Paclitaxel (or Taxol (R)) is a first-line chemotherapeutic drug for the treatment of non-small cell lung cancer; however, resistance to the drug is an important factor, which influences the outcome of chemotherapy. The present study aimed to investigate the role of triptolide (TPL) in reversing Taxol-resistant human lung adenocarcinoma and to elucidate the underlying molecular mechanism of resistance reversal mediated by TPL. It was hypothesized that this experimental approach would assist in solving the problem of chemotherapeutic resistance in non-small cell lung cancer, thereby improving the clinical outcomes. The human Taxol-resistant lung adenocarcinoma cell line, A549/Taxol, was established. The resistance index of the cell line was calculated, according to the half maximal inhibitory concentration (IC50) of A549/Taxol IC50 of A549, to be 51.87. The levels of apoptosis and the cell cycle in the A549/Taxol cell line were assessed to confirm the effects of TPL at three different concentrations (0.03, 0.3 and 3 mu mol/1) and treatment durations (2, 4, 6 and 12 h) by flow cytometric analysis, and the inhibition of the NF-kappa B signaling pathway and the expression of NF-kappa B-regulated drug-resistant proteins were determined by immunofluorescence and western blotting, respectively. The administration of TPL promoted cell apoptosis in the A549/Taxol lung adenocarcinoma Taxol-resistant cell line and also promoted cell cycle regulation. The drug was also able to elicit a reversal of the drug resistance. TPL inhibited the nuclear factor-kappa B (NF-kappa B) signaling pathway and the expression of NF-kappa B-regulated drug-resistant genes, including those for FLICE-like inhibitory protein, X-linked inhibitor of apoptosis protein, Bcl-2, Bcl-xL and cyclo-oxygenase-2. TPL exerted a marked drug-resistance-reversal effect on human lung adenocarcinoma Taxol resistance, and the effect was revealed to be dose- and time-dependent. In conclusion, TPL exerted its role in the process of resistance reversal by inhibiting the NF-kappa B signaling pathway, and the transcription and expression of NF-kappa B-regulated drug-resistant genes.