fucoxanthin and Stomach-Neoplasms

Lymph node metastasis is a key mechanism in gastric cancer (GC) metastasis and lymphangiogenesis is a vital step in the process of lymph node metastasis. Currently, there are no drugs which can treat lymph node metastasis in GC. Previous studies using the drug fucoxanthin have mainly focused on cell cycle arrest, induction of apoptosis, or inhibition of angiogenesis in GC. However, the effects of fucoxanthin on lymphangiogenesis and metastasis in GC have not been studied.. Cell counting kit 8 and transwell experiments were used to evaluate the inhibitory effect of fucoxanthin on cell proliferation, migration and invasion. HGC-27 and HLEC cells were co-cultured in a transwell chamber and the footpad metastasis model was established to evaluate lymphangiogenesis and lymph node metastasis. The possible regulatory targets of fucoxanthin in GC were analyzed using human tissue microarrays, bioinformatics analysis, and molecular docking. The regulatory pathway of fucoxanthin was verified using confocal laser microscopy, adenovirus transfection and western blotting.. Tissue microarray and bioinformatics analyses showed that Ran was highly expressed in metastatic lymph nodes and has some predictive value for metastasis in GC. Molecular docking results revealed that fucoxanthin interacted with Met189 and Lys167 of Ran via hydrogen bonds. Mechanistically, fucoxanthin inhibits the nuclear transport of NF-κB by downregulating protein expression of Ran and importinβ, thereby inhibiting VEGF-C secretion, and ultimately inhibiting tumor lymphangiogenesis and lymph node metastasis in vivo and in vitro.. Fucoxanthin suppressed GC-induced lymphangiogenesis and metastasis in vitro and in vivo by regulating Ran expression via the importinβ/NF-κB/VEGF-C nuclear transport signaling pathway. These novel findings provide the basis for the research and development of novel treatments using traditional Chinese medicine in treatment of lymph node metastasis, which has important theoretical significance and clinical value.

Topics: Cell Line, Tumor; Humans; Lymphangiogenesis; Lymphatic Metastasis; Molecular Docking Simulation; NF-kappa B; Stomach Neoplasms; Vascular Endothelial Growth Factor C

Fucoxanthin is a natural carotenoid that had never been previously demonstrated to have anti-tumor effect on human gastric adenocarcinoma SGC-7901 or BGC-823 cells. Here it was found to inhibit proliferation and induce apoptosis through JAK/STAT signal pathway in these cells; the mechanism by which this occurred was investigated. We find that fucoxanthin significantly increased the number of apoptotic cells by propidium iodide (PI) dye staining and flow cytometry. Fucoxanthin (50 or 75 μM) induced SGC-7901 cells cycle arrest at S phase, while BGC-823 cells arrest at G2/M phase. RT-PCR and western blot analysis revealed that the expressions of Mcl-1, STAT3 and p-STAT3 were obviously decreased by fucoxanthin in a dose-dependent manner. Synthetic siRNA targeting Mcl-1 was transfected into cells which had no effect on expressions of STAT3. After pretreatment with AG490 (50 μM) which led to blocking of the JAK/STAT signal pathway, the reductive expressions of Mcl-1, STAT3 and p-STAT3 caused by fucoxanthin were inhibited. This is the first analysis of effects on SGC-7901 and BGC-823 cells by fucoxanthin. Fucoxanthin can induce cell-cycle arrest and apoptosis in these cells. These effects involved downregulation of Mcl-1, STAT3 and p-STAT3. This work is significant for better understanding of mechanisms leading to human gastric adenocarcinoma formation and informing exploitation of anti-tumor marine drug, and for providing Mcl-1 and STAT3 as potential therapeutic targets for gastric adenocarcinoma.

Topics: Adenocarcinoma; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Down-Regulation; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Phaeophyceae; Signal Transduction; STAT3 Transcription Factor; Stomach Neoplasms; Xanthophylls

Autophagy and apoptosis are involved in the development of a variety of cancers. Fucoxanthin is a natural compound known to have antitumor effects, so we aimed to explore its effects on autophagy and apoptosis in gastric cancer SGC7901 cells. Specifically, we performed methyl thiazolyl tetrazolium assay, transmission electron microscopy, real-time polymerase chain reaction, Western blot analysis, immunofluorescence assay, and cell apoptosis analysis to clarify the role of fucoxanthin in SGC-7901 cells. Our results indicate that fucoxanthin significantly inhibits the viability of SGC-7901 cells, effectively inducing both autophagy and apoptosis by up-regulating the expressions of beclin-1, LC3, and cleaved caspase-3 (CC3), and by down regulating Bcl-2. Fucoxanthin-induced autophagy also seems to occur before, and may promote apoptosis.

Topics: Antineoplastic Agents; Apoptosis; Autophagy; Beclin-1; Caspase 3; Cell Line, Tumor; Cell Survival; Humans; Microtubule-Associated Proteins; Phaeophyceae; Signal Transduction; Stomach Neoplasms; Time Factors; Xanthophylls

In this study, we investigated the anti-tumor effects and possible mechanisms of fucoxanthin, which has been reported to inhibit tumor proliferation and induce apoptosis in vitro or in vivo. Human gastric adenocarcinoma MGC-803 cells were treated with fucoxanthin (25μM, 50μM or 75μM). Data of flow cytometry revealed that fucoxanthin (50μM or 75μM) increased the ratio of cell in G2/M phase and apoptotic MGC-803 cells varying on a dose-dependent manner. Results from reverse transcriptase-polymerase chain reaction and Western blot showed that treatment with fucoxanthin (50μM or 75μM) significantly decreased the expressions of CyclinB1, survivin and STAT3 in MGC-803 cells in a dose-dependent manner both at the time of 24h and 48h. In addition, immunofluorescence microscopy analysis also revealed the suppressed expressions of CyclinB1 and survivin by fucoxanthin. After pretreatment with AG490 (the inhibitor for JAK/STAT signal pathway), the expressions of p-STAT3 and survivin remained also slightly lower than the vehicle control group. Co-treated with fucoxanthin (75μM) and AG490, the reduction on the expressions of STAT3, p-STAT3 and CyclinB1 by fucoxanthin were attenuated while that of survivin was enhanced. Taken together, fucoxanthin can down-regulate the expressions of CyclinB1 and survivin, inducing cell cycle arrest in G2/M phase, and apoptosis in MGC-803 cells. The reduction of CyclinB1 by fucoxanthin was associated with JAK/STAT signal pathway.

Topics: Adenocarcinoma; Apoptosis; Cell Division; Cell Line, Tumor; Cell Proliferation; Cyclin B1; G2 Phase; Gene Expression Regulation, Neoplastic; Humans; Inhibitor of Apoptosis Proteins; Janus Kinases; Signal Transduction; STAT Transcription Factors; STAT3 Transcription Factor; Stomach Neoplasms; Survivin; Xanthophylls

We have reported that fucoxanthin, a natural carotenoid, inhibited the growth of human neuroblastoma GOTO cells. In the present study, we show that a metabolite of fucoxanthin, halocynthiaxanthin, which is isolated from sea squirt Halocynthia roretzi, has a more potent inhibitory effect. Halocynthiaxanthin (5 micrograms/ml) caused complete suppression of GOTO cell proliferation, whereas fucoxanthin reduced the growth rate by only 88.8% compared with the control, at day 2 after the drug treatment. Furthermore, halocynthiaxanthin also inhibited the growth of other human malignant tumor cells. Thus halocynthiaxanthin seems to be a promising anti-neoplastic agent.

Topics: Antineoplastic Agents; Carotenoids; Cell Division; Colonic Neoplasms; DNA, Neoplasm; Food; Gene Expression; Genes, myc; HeLa Cells; Humans; Kinetics; Neoplasm Proteins; Neuroblastoma; Pancreatic Neoplasms; RNA, Neoplasm; Stomach Neoplasms; Tumor Cells, Cultured; Xanthophylls