fucoxanthin and Adenocarcinoma

Fucoxanthin (Fx), a marine carotenoid found in edible brown algae, is well known for having anticancer properties. The gut microbiota has been demonstrated as a hallmark for colorectal cancer progression in both humans and rodents. However, it remains unclear whether the gut microbiota is associated with the anticancer effect of Fx. We investigated the chemopreventive potency of Fx and its effect on gut microbiota in a mouse model of inflammation-associated colorectal cancer (by azoxymethane/dextran sulfate sodium treatment). Fx administration (30 mg/kg bw) during a 14 week period significantly inhibited the multiplicity of colorectal adenocarcinoma in mice. The number of apoptosis-like cleaved caspase-3high cells increased significantly in both colonic adenocarcinoma and mucosal crypts. Fx administration significantly suppressed Bacteroidlales (f_uc; g_uc) (0.3-fold) and Rikenellaceae (g_uc) (0.6-fold) and increased Lachnospiraceae (g_uc) (2.2-fold), compared with those of control mice. Oral administration of a fecal suspension obtained from Fx-treated mice, aimed to enhance Lachnospiraceae, suppress the number of colorectal adenocarcinomas in azoxymethane/dextran sulfate sodium-treated mice with a successful increase in Lachnospiraceae in the gut. Our findings suggested that an alteration in gut microbiota by dietary Fx might be an essential factor in the cancer chemopreventive effect of Fx in azoxymethane/dextran sulfate sodium-treated mice.

Topics: Adenocarcinoma; Animals; Azoxymethane; Colitis-Associated Neoplasms; Colitis, Ulcerative; Dextran Sulfate; Disease Models, Animal; Drug Screening Assays, Antitumor; Feces; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Male; Mice; Xanthophylls

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

Pregnane X receptor (PXR) has been reported to regulate the expression of drug-metabolizing enzymes, such as the cytochrome P450 3A (CYP3A) family and transporters, such as multiple drug resistance 1 (MDR1). Fucoxanthin, the major carotenoid in brown sea algae, is a putative chemopreventive agent. In this study, we determined whether fucoxanthin could overcome drug resistance through attenuation of rifampin-induced CYP3A4 and MDR1 gene expression by PXR-mediated pathways in HepG2 hepatoma cells. We found that fucoxanthin (1-10 μM) significantly attenuated rifampin (20 μM)-induced CYP3A4, MDR1 mRNA and CYP3A4 protein expression at 24 h of incubation. Mechanistically, fucoxanthin strongly attenuated the PXR-mediated CYP3A4 promoter activity in HepG2 cells. In addition, fucoxanthin attenuated constitutive androstane receptor (CAR)- and rPXR-mediated CYP3A4 promoter activity in this cell line. Using the mammalian two-hybrid assay, we found that fucoxanthin significantly decreased the interaction between PXR and SRC-1, a PXR co-activator. Thus, fucoxanthin can decrease rifampin-induced CYP3A4 and MDR1 expression through attenuation of PXR-mediated CYP3A4 promoter activation and interaction between PXR and co-activator. These findings could lead to potentially important new therapeutic and dietary approaches to reduce the frequency of adverse drug reactions.

Topics: Adenocarcinoma; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Colonic Neoplasms; Constitutive Androstane Receptor; Cytochrome P-450 CYP3A; Hep G2 Cells; Humans; Pregnane X Receptor; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Rifampin; RNA, Messenger; Transcriptional Activation; 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