A hybrid of coumarin and phenylsulfonylfuroxan induces caspase-dependent apoptosis and cytoprotective autophagy in lung adenocarcinoma cells.

Lung adenocarcinoma is the most primary histologic subtype of non-small cell lung cancer (NSCLC). Compound 8b, a novel coumarin derivative with phenylsulfonylfuroxan group, shows significant antiproliferation activity against lung adenocarcinoma cell with low toxicity. This study aims to uncover the potential of compound 8b in relation to apoptosis as well as autophagy induction in lung adenocarcinoma cells. The cytotoxicity and apoptosis of A549 and H1299 cells induced by compound 8b were detected by MTT, microscope and western blot analysis. Autophagy was determined by TEM, confocal microscopy and western blot analysis. Akt/mTOR and Erk signaling pathway were also examined by western blot analysis. First, significant growth inhibition and caspase-dependent apoptosis were observed in compound 8b-treated A549 and H1299 cells. Then, we confirmed compound 8b-induced autophagy by autophagosomes formation, upregulated expression of autophagy-related protein LC3-II and autophagic flux. Importantly, abolishing autophagy using inhibitors and ATG5 siRNA enhanced the cytotoxicity of compound 8b, indicating the cytoprotective role of autophagy in lung adenocarcinoma. Further mechanistic investigations suggested that Akt/mTOR and Erk signaling pathways contributed to autophagy induction by compound 8b. This results demonstrate that compound 8b induces caspase-dependent apoptosis as well as cytoprotective autophagy in lung adenocarcinoma cells, which may provide scientific evidence for developing this furoxan-based NO-releasing coumarin derivative as a potential anti-lung adenocarcinoma therapeutic agents.

Wang Q ，Guo Y ，Jiang S ，Dong M ，Kuerban K ，Li J ，Feng M ，Chen Y ，Ye L ... -  《-》

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 ... -  《-》

Autophagy facilitates lung adenocarcinoma resistance to cisplatin treatment by activation of AMPK/mTOR signaling pathway.

Wu T ，Wang MC ，Jing L ，Liu ZY ，Guo H ，Liu Y ，Bai YY ，Cheng YZ ，Nan KJ ，Liang X ... -  《-》

Cabazitaxel-induced autophagy via the PI3K/Akt/mTOR pathway contributes to A549 cell death.

Huo R ，Wang L ，Liu P ，Zhao Y ，Zhang C ，Bai B ，Liu X ，Shi C ，Wei S ，Zhang H ... -  《-》

Brevilin A induces apoptosis and autophagy of colon adenocarcinoma cell CT26 via mitochondrial pathway and PI3K/AKT/mTOR inactivation.

Brevilin A is a sesquiterpene lactone isolated from Centipeda minima and possesses inhibitory effects on proliferation of various tumor cells. In this study, Brevilin A inhibitory effect on proliferation and its molecular mechanism of action were investigated both in vivo and in vitro in colon adenocarcinoma CT26 cells. The results indicated that the inhibitory effect of Brevilin A in CT26 proliferation was dose-dependent and this effect was due to apoptosis. Furthermore, Brevilin A increased ROS levels, decreased mitochondrial membrane potential (MMP) and induced apoptosis of CT26 cell in a dose-dependent manner. Apoptosis induced by Brevilin A was higher than that induced by adriamycin under the same dose. Cleaved-caspase-8, cleaved-caspase-9 and cleaved-caspase-3 were up-regulated after Brevilin A treatment, together with an increase of Bax protein expression, while Bcl-2 was reduced. Further investigation revealed that Brevilin A inhibited the phosphorylation of PI3K, AKT and mTOR and promoted the expressions of autophagy-related proteins LC3-II, Beclin1 and Atg5 and consequent formation of autophagosomes, whereas 3-methyladenine (3-MA), a type III PI3K inhibitor, inhibited autophagosomes formation induced by Brevilin A. In vivo investigation suggested that Brevilin A significantly inhibited the growth of CT26 tumor compared to adriamycin and concurrently promoted the expressions of LC3-II and cleaved-caspase-3 in tumor tissues. Our results demonstrated that the anti-tumor activity of Brevilin A was mainly achieved by the induction of cell apoptosis and autophagy, suggesting a promising potential as antitumor drug against colon adenocarcinoma.

You P ，Wu H ，Deng M ，Peng J ，Li F ，Yang Y ... -  《-》