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

Abstract

Paclitaxel (or Taxol®) 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 µmol/l) and treatment durations (2, 4, 6 and 12 h) by flow cytometric analysis, and the inhibition of the NF-κB signaling pathway and the expression of NF-κB-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-κB (NF-κB) signaling pathway and the expression of NF-κB-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-κB signaling pathway, and the transcription and expression of NF-κB-regulated drug-resistant genes.

Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF‑7 cells

“…The change in cell viability was confirmed via flow cytometry assay, and morphology variation was observed by fluorescent staining with Hoechst 33258 and Annexin V-FITC/PI, consistent with previous reports (25). Much research has focused on the ability of TPI to inhibit proliferation and migration of tumors, and its potential applications in drug resistance and radiation/chemotherapy sensitization (26). The anti-cancer mechanisms of TPI have been shown to be related to multiple signals and pathways, including the estrogen receptor signaling pathway (25) and phospholipase D1 expression (27).…”

Triptolide induces cell apoptosis in human stomach cancer cell via caspase 3-dependent cascade pathway

“…Triptolide exerts potent anti-cancer effects in several cancer types including lung cancer [10], liver cancer [11], pancreatic cancer [12], and colon cancer [13]. In our present study, we demonstrated that triptolide exhibited promising anti-cancer potential in human gastric BGC-823 cells.…”

“…Our results showed that toxic effects were increased in BGC-823 cells by triptolide treatment (10,20, and 40 nM) in a dosedependent manner (Figure 2). …”

“…The cells at a density of 5 × 10 4 cells/mL were seeded in 96-well plates and treated with various concentrations of triptolide (10,20, and 40 nM) or vehicle solution (0.1 % DMSO) for 48 or 72 h. Then, 20 μL of MTT (5 mg/mL) solution was added into each well and incubated for another 4 h. After replacing the culture medium with 100 μL of DMSO, the optical density (OD) was collected at the wavelength of 540 nm using a microplate reader (TECAN, Austria).…”

“…Triptolide is one of the active diterpene triepoxide compound identified from Trypterigium wilfordii Hook L. To date, triptolide has been found to exert potent immunosuppressive and anti-inflammatory properties [9]. Triptolide is also demonstrated to have anti-cancer effects in several cancer types including lung cancer [10], liver cancer [11], pancreatic cancer [12], and colon cancer [13]. In addition, triptolide is also able to cause pancreatic cancer cell death through induction of apoptosis via inhibition of HSP70 [12].…”