Curcumin potentiates the galbanic acid-induced anti-tumor effect in non-small cell lung cancer cells through inhibiting Akt/mTOR signaling pathway.

Galbanic acid (GBA), which is known as a sesquiterpene coumarin, has been reported to have various anti-tumor activities in different cells. Our study intended to investigate whether curcumin potentiates GBA-induced anti-tumor effect in non-small cell lung cancer cells. The combined effect of GBA and curcumin on cell viability was examined by MTT analysis. Cellular apoptosis was evaluated by flow cytometry analysis. Autophagy was defined by autophagosome observed by confocal microscopy after infected with GFP-LC3 adenovirus. In addition, the expression of marker proteins involved in cell apoptosis, autophagy, and Akt/mTOR signaling pathway were estimated by qRT-PCR and Western Blotting assay. 15 μM curcumin combined with 40 μM GBA could obtain better synergistic repressive efficacy on cell viability and notably induced cell apoptosis in A549 cells. Besides, curcumin in alliance with GBA could significantly inhibit cell migration and invasion. GFP-LC3 infection experiments elaborated that curcumin could potentiate GBA induced cell autophagy and restrain the phosphorylation of Akt/mTOR/P70s6k signaling pathway. What's more, the reaction of migration, apoptosis, and autophagy induced by curcumin and GBA treatment could be reversed by mTOR inhibitor rapamycin and AKT activator insulin.

Zhang Q ，Qiao H ，Wu D ，Lu H ，Liu L ，Sang X ，Li D ，Zhou Y ... -  《-》

Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway.

Liu F ，Gao S ，Yang Y ，Zhao X ，Fan Y ，Ma W ，Yang D ，Yang A ，Yu Y ... -  《-》

A novel hybrid of 3-benzyl coumarin seco-B-ring derivative and phenylsulfonylfuroxan induces apoptosis and autophagy in non-small-cell lung cancer.

Compound 6, as a novel hybrid of 3-benzyl coumarin seco-B-ring derivative and nitric oxide (NO) donor phenylsulfonylfuroxan, has the potential to develop into an anticancer drug because it displays significant antiproliferation activitity for various solid cancer cell lines including non-small-cell lung cancer (NSCLC) cells. We attempt to uncover the capacities of compound 6 to induce apoptosis and autophagy in NSCLC cells, as well as the underlying mechanism involved in this process. The effect of compound 6 on cell viability was evaluated in A549 cells by MTT assay. Apoptosis was mainly detected by flow cytometry. The induction of autophagy was observed by transmission electron microscopy (TEM), confocal microscopy as well as western-blotting technique. The expression of all related-proteins including PI3K/Akt/mTOR signaling pathway were also examined by western-blotting technique. Above all, distinct growth inhibition and caspase-dependent apoptosis were detected in A549 cells administered with compound 6. Then, we confirmed the induction of autophagy triggered by compound 6 in A549 cells. Noticeably, blocking autophagy using a series of inhibitors and ATG5 siRNA had little effect on the cytotoxicity of compound 6, elucidating nonprotective autophagy triggered in NSCLC cells. Further research illustrated that PI3K/Akt/mTOR signaling pathway was involved in compound 6-induced apoptosis, and 3-MA as well as LY294002 had synergistic inhibiting effect on proliferation of A549 cells through the pathway mentioned above. These findings raise a rationale that this 3-benzyl coumarin seco-B-ring derivative and phenylsulfonylfuroxan hybrid could be a promising candidate for developing as a therapeutic agent toward NSCLC, and the combination therapy through PI3K/Akt/mTOR signaling pathway may result in optimized treatment outcomes.

Dong M ，Ye T ，Bi Y ，Wang Q ，Kuerban K ，Li J ，Feng M ，Wang K ，Chen Y ，Ye L ... -  《-》

Luteoloside induces G(0)/G(1) arrest and pro-death autophagy through the ROS-mediated AKT/mTOR/p70S6K signalling pathway in human non-small cell lung cancer cell lines.

Autophagy has attracted a great deal of interest in tumour therapy research in recent years. However, the anticancer effect of luteoloside, a naturally occurring flavonoid isolated from the medicinal plant Gentiana macrophylla, on autophagy remains poorly understood in human lung cells. In the present study, we have investigated the anticancer effects of luteoloside on non-small cell lung cancer (NSCLC) cells and demonstrated that luteoloside effectively inhibited cancer cell proliferation, inducing G0/G1 phase arrest associated with reduced expression of CyclinE, CyclinD1 and CDK4; we further found that treatment with luteoloside did not strongly result in apoptotic cell death in NSCLC (A549 and H292) cells. Interestingly, luteoloside induced autophagy in lung cancer cells, which was correlated with the formation of autophagic vacuoles, breakdown of p62, and the overexpression of Beclin-1 and LC3-II, but not in a human bronchial epithelial cell line (BEAS-2B). Notably, pretreatment of cancer cells with 3-MA, an autophagy inhibitor, protected against autophagy and promoted cell viability but not apoptosis. To further clarify whether luteoloside-induced autophagy depended on the PI3K/AKT/mTOR/p70S6K signalling pathway, a major autophagy-suppressive cascade, cells were treated with a combination of AKT inhibitor (LY294002) and mTOR inhibitor (Rap). These results demonstrated that luteoloside induced autophagy in lung cancer cell lines by inhibiting the pathway at p-Akt (Ser473), p-mTOR and p-p70S6K (Thr389). Moreover, we observed that luteoloside-induced cell autophagy was correlated with production of reactive oxygen species (ROS). NAC-mediated protection against ROS clearly implicated ROS in the activation of autophagy and cell death. In addition, the results showed that ROS served as an upstream effector of the PI3K/AKT/mTOR/p70S6K pathway. Taken together, the present study provides new insights into the molecular mechanisms underlying luteoloside-mediated cell death in NSCLC cells and supports luteoloside as a potential anti-cancer agent for targeting NSCLC through the induction of autophagy, inhibition of proliferation and PI3K/AKT/mTOR/p70S6K signalling.

Zhou M ，Shen S ，Zhao X ，Gong X ... -  《-》

Curcumin inhibits migration and invasion of non-small cell lung cancer cells through up-regulation of miR-206 and suppression of PI3K/AKT/mTOR signaling pathway.

Wang N ，Feng T ，Liu X ，Liu Q ... -  《-》