Abstract
Objective: Costunolide (Cos) is a sesquiterpene lactone extracted from chicory. Although it possesses anti-tumor effects, the underlying molecular mechanism against gastric cancer cells remains unclear. This study aimed to explore the effect and potential mechanism of Cos on gastric cancer.Methods: The effect of Cos on HGC-27 and SNU-1 proliferation was detected by CCK-8 and clone formation assay. The changes in cell apoptosis were determined using Hoechst 33258 and tunel staining. The morphology of autophagy was analyzed by autophagosomes with the electron microscope and LC3-immunofluorescence with the confocal microscope. The related protein levels of the cell cycle, apoptosis, autophagy and AKT/GSK3β pathway were determined by Western blot. The anti-tumor activity of Cos was evaluated by subcutaneously xenotransplanting HGC-27 into Balb/c nude mice. The Ki67 and P-AKT levels were examined by immunohistochemistry.Results: Cos significantly inhibited HGC-27 and SNU-1 growth and induced cell cycle arrest in the G2/M phase. Cos activated intrinsic apoptosis and autophagy through promoting cellular reactive oxygen species (ROS) levels and inhibiting the ROS-AKT/GSK3β signaling pathway. Moreover, preincubating gastric carcinoma cells with 3-methyladenine (3-MA), a cell-autophagy inhibitor, significantly alleviated the effects of Cos in inducing cell apoptosis.Conclusion: Cos induced apoptosis of gastric carcinoma cells via promoting ROS and inhibiting AKT/GSK3β pathway and activating pro-death cell autophagy, which may be an effective strategy to treat gastric cancer.
Highlights
Gastric cancer (GC), one of the most common malignancies worldwide, is the third leading cause of cancer deaths worldwide (Bray et al, 2018), with more than half of the cases occurring in East Asia especially in China, Japan, and South Korea (Rahman et al, 2014)
The results showed that Cos inhibited HGC-27 and SNU-1 cell growth and induced apoptosis and autophagy via the Reactive oxygen species (ROS)-AKT/glycogen synthase kinase-3β (GSK3β) pathway and induced apoptosis through activating pro-death autophagy, which provides experimental support and a theoretical basis for further research on the role of Cos in gastric cancer treatment
The results showed that tumor volume and weight in 30 mg/kg and 50 mg/kg Cos were significantly reduced compared with the dimethyl sulfoxide (DMSO) group, especially in the 50 mg/kg group (p < 0.01), but both of them increased compared to the Cisplatin group (Figures 10A–C)
Summary
Gastric cancer (GC), one of the most common malignancies worldwide, is the third leading cause of cancer deaths worldwide (Bray et al, 2018), with more than half of the cases occurring in East Asia especially in China, Japan, and South Korea (Rahman et al, 2014). More than half of the gastric cancer patients undergoing radical resection developed local recurrence or distant metastasis, and the prognosis is generally poor (Efferth et al, 2008). Another important problem in tumor chemotherapy is the development of drug resistance and side effects (Turner et al, 2012), so that most patients with gastric cancer share a poor quality of life, with a survival time of less than 5 years in a majority of cases (Suzuki et al, 2016). Novel drugs against gastric cancer with low toxicity and high potency need to be developed urgently in the clinic
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