plastochromanol-8 and Stomach-Neoplasms

Gastric cancer is a common cause of death from cancer and an important global health care issue. Consequently, there is an urgent need to find new drugs and therapeutic targets for the treatment of gastric cancer. Recent studies have shown that tocotrienols (T3) have significant anticancer ability in cancer cell lines. Our previous study found that γ-tocotrienol (γ-T3) induced apoptosis in gastric cancer cells. We further explored the possible mechanisms of γ-T3 therapy for gastric cancer.. In this study, we treated gastric cancer cells with γ-T3, collect and deposit the cells. γ-T3-treated gastric cancer cells group and untreated group were subjected to RNA-seq assay, and analysis of sequencing results.. Consistent with our previous findings, the results suggest that γ-T3 can inhibit mitochondrial complexes and oxidative phosphorylation. Analysis reveals that γ-T3 has altered mRNA and ncRNA in gastric cancer cells. Significantly altered signaling pathways after γ-T3 treatment were enriched for human papillomavirus infection (HPV) pathway and notch signaling pathway. The same significantly down-regulated genes notch1 and notch2 were present in both pathways in γ-T3-treated gastric cancer cells compared to controls.. It is indicated that γ-T3 may cure gastric cancer by inhibiting the notch signaling pathway. To provide a new and powerful basis for the clinical treatment of gastric cancer.

Topics: Apoptosis; Cell Line, Tumor; Humans; Signal Transduction; Stomach Neoplasms; Tocotrienols; Vitamin E

γ-Tocotrienol (γ-T3) exhibits the activity of anticancer via regulating cell signaling pathways. Nuclear factor-κB (NF-κB), one of the crucial pro-inflammatory factors, is involved in the regulation of cell proliferation, apoptosis, invasion, and migration of tumor. In the present study, NF-κB activity inhibited by γ-T3 was investigated in gastric cancer cells. Cell proliferation, NF-κB activity, active protein phosphatase type 2A (PP2A), and ataxia-telangiectasia mutated (ATM) protein were explored using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT), methylene blue, enzyme-linked immunosorbent assay (ELISA), malachite green, luciferase, and Western blotting assays. The effects of γ-T3 on tumor growth and the expression of NF-κB and PP2A proteins were also further examined by implanting human gastric cancer cells in a BALB/c nude mouse model. The results showed that γ-T3 significantly inhibited the cell proliferation and attenuated the NF-κB activity in vitro and in vivo. γ-T3 dramatically increased PP2A activity and protein expression, which suppressed ATM phosphorylation and its translocation to the cytoplasm in gastric cancer cells. Thus, our findings may provide mechanistic insight into effects of γ-T3 on the regulation of NF-κB activity by a PP2A-dependent mechanism and suggest that PP2A may serve as a molecular target for a potential chemopreventive agent.

Topics: Animals; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Cell Line, Tumor; Cell Proliferation; Chromans; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Protein Phosphatase 2; Stomach Neoplasms; Vitamin E

γ-tocotrienol (γ-T3), a tocotrienol isoform belonging to the vitamin E family, has been revealed to exert inhibitory effects on proliferation, migration and invasion in human gastric cancer cells. However, its precise mechanism of action is still unclear and needs to be further tested. Cyclooxygenase-2 (COX-2) is well known for its key role in promoting the migration and invasion abilities of human gastric cancer cells. In light of these data, our study aimed to validate whether the inhibitory actions of γ-T3 could be achieved by downregulation of COX-2 activity in vitro. In the present study, a Cell Counting Kit-8 (CCK-8) assay was performed to observe proliferation in human gastric cancer cells (SGC-7901 and MGC-803 cells), and wound healing and Transwell chamber assays were performed to detect migration and invasion. Western blot analyses were performed to analyse the relative expression of COX-2, matrix metalloproteinases-2 and -9 (MMP-2 and MMP-9) proteins, and enzyme-linked immunosorbent assays (ELISA) were used to determine the exocrine roles of MMP-2 and MMP-9. The results revealed that γ-T3 exerted significant inhibitory effects on proliferation, migration, invasion and COX-2 protein expression, as well as on exocrine functions of MMP-2 and MMP-9 in SGC-7901 and MGC-803 cells. Therefore, our results indicated that γ-T3 exerts inhibitory effects on migration and invasion, which may be mediated through downregulation of COX-2 expression in SGC-7901 and MGC-803 cells.

Topics: Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromans; Cyclooxygenase 2; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Stomach Neoplasms; Vitamin E

Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether γ-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.. The effect of γ-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-κB activation by DNA-binding assay, and gene expression by Western blotting. The effect of γ-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.. γ-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-κB, and suppressed the NF-κB-regulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of γ-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and γ-tocotrienol. As compared with vehicle control, γ-tocotrienol also suppressed the NF-κB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.. Overall our results show that γ-tocotrienol can potentiate the effects of capecitabine through suppression of NF-κB-regulated markers of proliferation, invasion, angiogenesis, and metastasis.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Capecitabine; Cell Line, Tumor; Cell Proliferation; Chromans; Cyclin D1; Cyclooxygenase 2; Deoxycytidine; Disease Models, Animal; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Intercellular Adhesion Molecule-1; Ki-67 Antigen; Matrix Metalloproteinase 9; Mice; Mice, Nude; Mitochondria; Neovascularization, Pathologic; NF-kappa B; Platelet Endothelial Cell Adhesion Molecule-1; Proto-Oncogene Proteins c-bcl-2; Receptors, CXCR4; Repressor Proteins; Stomach Neoplasms; Survivin; Vascular Endothelial Growth Factor A; Vitamin E; Xenograft Model Antitumor Assays

Natural vitamin E is a mixture of two classes of compounds, tocopherols and tocotrienols. Recent research has revealed that tocotrienols, especially gamma-tocotrienol, exhibit not only the same antioxidant ability as tocopherols, but also remarkable anticancer capacity in cancer cell lines. In this study, the invasion and metastatic capacities of gastric adenocarcinoma SGC-7901 cells and the correlation with antimetastasis mechanisms induced by gamma-tocotrienol were explored. The results showed the inhibitory effects of gamma-tocotrienol at doses of 15, 30, 45 and 60 mumol/L for 48 h on cell migration and cell matrigel invasion; activities of matrix metalloproteinase (MMPs) increased in SGC-7901 cells when compared to the control group (P<.05 or P<.01). An increasing trend in the chemotactic responses to fibronectin (FN) in SGC-7901 cells was found in the gamma-tocotrienol treatments. SGC-7901 cell attachment decreased in the gamma-tocotrienol-treated groups in comparison with the control group (P<.01). The mRNA expressions of MMP-2 and MMP-9 showed that gamma-tocotrienol significantly reduced the matrigel invasion capability through down-regulation of the mRNA expressions of MMP-2 and MMP-9 (P<.01), and up-regulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 in SGC-7901 cells by treatment with gamma-tocotrienol for 48 h (P<.05). gamma-Tocotrienol also significantly increased the mRNA expression of nm23-H1 in SGC-7901 cells (P<.01). These findings suggest a potential mechanism of gamma-tocotrienol-mediated antitumor metastasis activity and indicate the role of vitamin E as potential chemopreventative agents against gastric cancer.

Topics: Adenocarcinoma; Antineoplastic Agents; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Survival; Chemotaxis; Chromans; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinases; Neoplasm Invasiveness; Neoplasm Metastasis; NM23 Nucleoside Diphosphate Kinases; Protein Isoforms; RNA, Messenger; Stomach Neoplasms; Time Factors; Tissue Inhibitor of Metalloproteinases; Vitamin E

Tocotrienols are naturally occurring isoprenoid compounds highly enriched in palm oil, rice bran, oat, wheat germ, barley and rye. Tocotrienols have antioxidant properties as well as potent anticancer properties. In this study, the mechanisms underlying the apoptosis of gamma-tocotrienol on human gastric adenocarcinoma SGC-7901 cells were further studied, especially in correlation with the involvement of the apoptotic pathway. gamma-Tocotrienol inhibited SGC-7901 cell growth in a concentration- and time-dependent manner. The inhibitory effects of SGC-7901 cells were correlated with the DNA damage and arresting cell cycle at G(0)/G(1) phase in a time-dependent manner at 60 mumol/L concentration of gamma-tocotrienol. gamma-Tocotrienol induced activation of caspase-3 and increased the cleavage of the downstream substrate poly(ADP-ribose) polymerase. Furthermore, gamma-tocotrienol-induced apoptosis on SGC-7901 cells was mediated by activation of caspase-9. The data in this study suggested that gamma-tocotrienol could induce the apoptosis on human gastric cancer SGC-7901 cells via mitochondria-dependent apoptosis pathway. Thus, our findings revealed gamma-tocotrienol as a potential, new chemopreventive agent for human gastric cancer.

Topics: Adenocarcinoma; Anticarcinogenic Agents; Antioxidants; Apoptosis; Caspase 3; Caspase 9; Cell Cycle; Cell Line, Tumor; Chromans; DNA Damage; Humans; Mitochondria; Poly(ADP-ribose) Polymerases; Stomach Neoplasms; Vitamin E

Tocotrienols have been shown to inhibit proliferation and induce apoptosis in cancer cells. However, the molecular mechanisms involved in tocotrienol-induced apoptosis are still unclear. In the present study, gamma-tocotrienol induced apoptosis in human gastric adenocarcinoma SGC-7901 cell line through down regulation of the extracellular signal-regulated kinase (ERK) signalling pathway. Furthermore, gamma-tocotrienol-induced apoptosis was accompanied by down regulation of Bcl-2, up regulation of Bax, activation of caspase-3, and subsequent poly (ADP-ribose) polymerase cleavage. These results indicated that up or down regulation of Bcl-2 family proteins play a major role in the initiation of gamma-tocotrienol-induced apoptosis as an activator of caspase-3. Gamma-tocotrienol also down regulated the activation of the Raf-ERK signalling pathway, and down regulated c-Myc by decreasing the expressions of Raf-1 and p-ERK1/2 proteins. The results suggest that key regulators in tocotrienol-induced apoptosis may be Bcl-2 families and caspase-3 in SGC-7901 cells through down regulation of the Raf-ERK signalling pathway.

Topics: Adenocarcinoma; Analysis of Variance; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspase 3; Cell Line, Tumor; Chromans; DNA Fragmentation; Down-Regulation; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-raf; Stomach Neoplasms; Vitamin E