Triptolide exerts pro-apoptotic and cell cycle arrest activity on drug-resistant human lung cancer A549/Taxol cells via modulation of MAPK and PI3K/Akt signaling pathways

Abstract

Abstract. Multidrug resistance (MDR) is a major obstacle in the effective chemotherapeutic treatment of cancers. Triptolide (TPL) is a diterpenoid isolated from Tripterygium wilfordii Hook. f., a traditional Chinese medicine. It was demonstrated in our previous study that TPL exerts anti-MDR cancers on various MDR cell lines (including A549/Taxol, MCF-7/ADR and Bel7402/5-Fu). The present study was designed to investigate its anti-proliferative activity on A549/Taxol cells, and explore the underlying mechanism of action. The anti-proliferative activity of TPL on A549/Taxol cells was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Its pro-apoptosis and cell cycle arrest activities were analyzed by flow cytometry. Western blot assay was employed to investigate the levels of mitogen-activated protein kinases (MAPKs) and apoptosis-related proteins in cells. TPL efficiently suppressed the proliferation of A549/Taxol cells. Co-treatment with MAPK inhibitors in the MTT assay indicated that the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways were involved in the process. Upregulation of p-p38, p-ERK, p-GSK-3β, Bax and cleaved caspases-3 and -9, and downregulation of p-JNK, p-Akt and Bcl-2 were observed upon treatment with TPL in the A549/Taxol cells. The results from flow cytometry assay revealed that TPL induced apoptosis and S-phase arrest in A549/Taxol cells. This occurred as a result of the upregulation of p-ERK and p-GSK-3β, and the downregulation of p-JNK and p-Akt, and was responsible for the subsequent anti-proliferative activity.

Triptolide-induced apoptosis in non-small cell lung cancer via a novel miR204-5p/Caveolin-1/Akt-mediated pathway

“…Also, our current data contradict previous reports [45] of unobserved apoptosis (despite ~50% cell death) in A549 cells treated for 24 h with 200 nM tripchlorolide, a derivative of TL. Moreover, our findings are in agreement with previous studies that have demonstrated activation of the Akt signaling pathway/apoptosis with similar time/TL dosage treatment of cancer cells [7], including A549 cells [46][47][48][49]. Overall, our study indicated that TL promoted apoptosis in NSCLC cells through Akt pathway signaling.…”

Polygalacin D induces apoptosis and cell cycle arrest via the PI3K/Akt pathway in non-small cell lung cancer

“…Apoptosis is one of the major goals of chemopreventive agents which inhibit the overall growth of cancer cells. Caspases are well-defined proteases related to apoptosis (17). Activation of caspase-3 and -9 induces the cleavage of PARP, eventually resulting in cell apoptosis.…”

Synergistic combination therapy of lung cancer using paclitaxel- and triptolide-coloaded lipid–polymer hybrid nanoparticles

“… 15 – 18 Its cytotoxic effect against NSCLC has been demonstrated in vitro and in vivo via the inhibition of nuclear factor (NF)-κB; upregulation of p-p38, p-ERK, p-GSK-3β, Bax, and cleaved caspases-3 and -9; and downregulation of p-JNK, p-Akt, and Bcl-2. 19 Moreover, TL exerts its anti-multidrug resistance (MDR) role on A549/Taxol cell lines by inhibiting the NF-κB signaling pathway and selective modulation of mitogen-activated protein kinase signaling. 20 , 21 However, TL has a poor solubility in water (0.017 mg/mL).…”