Original article
7-O-Geranylquercetin induces apoptosis in gastric cancer cells via ROS-MAPK mediated mitochondrial signaling pathway activation
Introduction
Gastric cancer is the second leading cause of cancer-related deaths and responsible for almost one million deaths worldwide per year [1]. The development of effective therapy for advanced gastric cancer is rather slow and no globally acceptable standard regimen has been established yet. At present, the disease still has a poor prognosis and remains a major health problem [2]. Therefore, new agents that have better activity on gastric cancer cells and less toxicity on normal cells are urgently needed.
Quercetin, a bioflavonoid, has attracted much attention in relation to its anticancer activities in many cancer cell models, such as colon [3], cervical carcinoma [4], breast [5], [6], [7], lymphoma, ovary, endometrium, prostate, liver and gastric cancers [8]. Studies have explored the mechanisms of quercetin-induced cell apoptosis in various cancer cell lines involving gastric cancer cell lines AGS [1] and BGC-823 [9], colon cancer cell lines HCT116 and HT-29 [3], cervical carcinoma HeLa cell line [4], breast cancer cell lines BT-474 [6] and MCF-7 [10]. Most of these works indicate that reactive oxygen species (ROS), mitogen‐activated protein kinase (MAPK) and mitochondria signaling pathways are involved in quercetin-induced apoptosis. Though quercetin has been studied extensively and profoundly as an antitumor agent, its clinical application is still seriously restricted by poor solubility and bioavailability.
7-O-Geranylquercetin (GQ) (Fig. 1) designed and synthesized by our group is a novel alkylated derivative of quercetin with better lipid solubility and higher antitumor activity than quercetin [11]. We have preliminarily demonstrated that the IC50 values of GQ against various human cancer cell lines were much lower than those of quercetin, including breast cancer cell line MCF-7, colon cancer cell line Caco-2, lung cancer cell lines NCI-H446 and A549, gastric cancer cell lines MGC-803 and SGC-7901 [11]. In addition, we have documented that GQ induced apoptosis in breast cancer cell line MCF-7 via a caspase-independent Endo G-mediated mitochondria pathway [12] and found that GQ induced autophagy and apoptosis via ROS generation in lung cancer cell lines A549 and NCI-H1975 (not published). Since GQ has broad antitumor spectrum and acts at different ways in breast cancer and lung cancer cells, it is necessary to illuminate the antitumor mechanisms of GQ in other cancer cells including gastric cancer cells.
In this study, we investigated the growth inhibition and apoptosis induction effects of GQ on human gastric cancer cell lines SGC-7901 and MGC-803, and explored the potential molecular mechanisms. This will make a molecular basis for developing GQ into a drug candidate for gastric cancer therapy and provide a reference for exploring the activities of GQ against other cancers.
Section snippets
Materials
GQ with the purity over 98% was prepared in our laboratory according the reported method [12]. Quercetin (purity > 98.5%) was purchased from the Aladdin Industrial Corporation (Shanghai, China). Acridineorange/ethidium bromide (AO/EB), 4′,6′-diamidino-2-phenyl-indole (DAPI), 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) were purchased from Sigma Chemical Corporation (St. Louis, MO, USA). Annexin V-FITC/propidium iodide (Annexin V-PI) staining kit, PI staining kit,
GQ inhibits cell viability in gastric cancer cells
MTT assay indicated that GQ inhibited the proliferation of SGC-7901 and MGC-803 cells in a dose- and time-dependent manner (Fig. 2A and B) and the growth inhibition effect of GQ was much stronger than that of quercetin. When SGC-7901 and MGC-803 cells were treated with 20 μM of GQ, the cell viabilities were about 22.6% and 23.6% after 24 h treatment, and then reduced to 11.9% and 9.3% after 48 h treatment, respectively. When the cells were objected to 40 μM of quercetin, the cell viabilities of
Discussion
The present study demonstrates that GQ, a novel O-alkylated derivate of quercetin, has stronger growth inhibition effect to human gastric cancer cell lines SGC-7901 and MGC-803 than quercetin, and reveals that GQ induces apoptosis through generating ROS and then successively activating MAPK and mitochondrial signal pathways in gastric cancer cells(Fig. 11).
In this study, we compared the cytotoxicity of GQ to gastric cancer cells and normal gastric epithelial cells. It was found that the growth
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgement
This work was financially supported by the Natural Science Foundation of Liaoning, China (201602217).
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The first two authors contributed equally to this paper.