fucoxanthin and Colonic-Neoplasms

Topics: Animals; Azoxymethane; Chemokines, CC; Colonic Neoplasms; Cyclin D1; Dextran Sulfate; Disease Models, Animal; Humans; Male; Mice; Mice, Inbred ICR; Proto-Oncogene Proteins c-akt; Receptors, CCR1; Smad2 Protein; Xanthophylls

Colorectal cancer therapy with 5-fluorouracil (5-Fu) frequently become ineffective due to resistance to this drug; and thus other effective compounds are essential for therapy. It is well-known marine brown seaweeds contain antioxidant compounds the carotenoid fucoxanthin (Fx) and polyphenolic compound phloroglucinol (Ph) which exerted diverse biological activities including antioxidant and anticancer. The aim of this study was to determine the anticancer activities of Fx or Ph alone as well as combination of each chemical with 5-Fu on two human colorectal cancer cell lines (HCT116 and HT29), with comparison to responses in a normal colon cell line (CCD-18Co). Effects of these compounds on cell viability, induction of DNA damage, and cell death were evaluated using MTT assay, comet assay, nuclear condensation assay, and Western blot. 5-Fu decreased cell viability in a concentration-dependent manner in HCT116 and HT29 cells but was not cytotoxic in CCD-18Co cells. 5-Fu induced DNA damage in HCT116 cells with induction of cell death, while no marked effects on DNA damage and cell death were observed in HT29 cells. Fx or Ph alone also reduced cell viability in both cancer cell lines but no apparent cytotoxic effect in CCD-18Co cells, except for Fx at 50 and 100 µM. Diminished cell viability was accompanied by induction of DNA damage (by Fx) and induction of cell death (by Ph). In combination with 5-Fu, Fx at 10 µM (in HCT116 and HT29 cells), and Ph at 300 µM (in HT29 cells) enhanced the cytotoxic effect of 5-Fu; however, no marked cytotoxicity was noted in CCD-18Co cells. Since Fx and Ph alone reduced cancer cell line viability without an effect on normal cells and when in combination enhanced the cytotoxic effect of 5-Fu only in colon cancer cells, these compounds seem promising as anticancer agents.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Blotting, Western; Cell Survival; Colon; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; HCT116 Cells; HT29 Cells; Humans; Phloroglucinol; Seaweed; Xanthophylls

Intestinal bacterial beta-glucuronidases are capable of retoxifying compounds that have been detoxified by liver glucuronidation and are also known to accelerate colon cancer invasion and metastasis. In this study, fucoxanthin extracted from the microalga Phaeodactylum tricornutum was investigated for its inhibitory activity against Escherichia coli beta-glucuronidase and DLD-1 cancer cells. Fucoxanthin inhibited beta-glucuronidase in a concentration-dependent manner with an IC50 value of 2.32 mM and a mixed inhibition type. Fucoxanthin had more potent inhibitory activity on beta-glucuronidase at 37 degrees C and in alkaline conditions. Fucoxanthin also inhibited the beta-glucuronidase activity of DLD-1 cancer cells at a concentration of 20-50 microM. The presence of beta-glucuronidase and substrate in the medium decreased the inhibitory activity of fucoxanthin against DLD-1 cancer cells. Therefore, microalgal fucoxanthin might prevent colon cancer because of its strong beta-glucuronidase inhibitory activity and could be utilized as a novel functional ingredient of food and pharmaceutical supplements.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Colonic Neoplasms; Glucuronidase; Humans; Microalgae; 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

Fucoxanthin, a natural carotenoid, has been reported to have antitumorigenic activity in mouse colon, skin and duodenum models. The present study was designed to evaluate the molecular mechanisms of fucoxanthin against colon cancer using the human colon adenocarcinoma cell lines. Fucoxanthin reduced the viability of WiDr cells in a dose-dependent manner accompanied by the induction of cell cycle arrest during the G0/G1 phase at 25 microM and apoptosis at 50 microM. Fucoxanthin at 25 microM inhibited the phosphorylation of the retinoblastoma protein (pRb) at Ser780 and Ser807/811 24 h after treatment without changes in the protein levels of the D-types of cyclin and cyclin-dependent kinase (cdk) 4, whose complexes are responsible for the phosphorylation of pRb at these sites. A cdk inhibitory protein, p21WAF1/Cip1 increased 24 h after the treatment with 25 microM of fucoxanthin, but not p27Kip1. In addition, the mRNA of p21WAF1/Cip1 also increased in a dose-dependent manner. According to the experiments using the isogenic human colon adenocarcinoma cell lines, fucoxanthin failed to induce G0/G1 arrest in the p21-deficient HCT116 cells, but not in HCT116 wild-type cells. All of these findings showed that fucoxanthin inhibited proliferation of colon cancer cells. The inhibitory mechanism is due to the cell cycle arrest during the G0/G1 phase mediated through the up-regulation of p21WAF1/Cip1, which may be related to the antitumorigenic activity.

Topics: Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; G1 Phase; HCT116 Cells; Humans; Phosphorylation; Resting Phase, Cell Cycle; Retinoblastoma Protein; Up-Regulation; Xanthophylls

The effect of fucoxanthin, from the edible seaweed Undaria pinnatifida on viability of colon cancer cells and induction of apoptosis was investigated. Fucoxanthin remarkably reduced the viability of human colon cancer cell lines, Caco-2, HT-29 and DLD-1. Furthermore, treatment with fucoxanthin induced DNA fragmentation, indicating apoptosis. The DNA fragmentation in Caco-2 cells treated with 22.6 microM fucoxanthin for 24 h was 10-fold higher than in the control. Fucoxanthin suppressed the level of Bcl-2 protein. Also, DNA fragmentation induced by fucoxanthin was partially inhibited by a caspase inhibitor Z-VAD-fmk. Moreover, combined treatment with 3.8 microM fucoxanthin and 10 microM troglitazone, which is a specific ligand for peroxisome proliferator-activated receptor (PPAR) gamma, effectively decreased the viability of Caco-2 cells. However, separate treatments with these same concentrations of fucoxanthin nor troglitazone did not affect cell viability. These findings indicate that fucoxanthin may act as a chemopreventive and/or chemotherapeutic carotenoid in colon cancer cells by modulating cell viability in combination with troglitazone.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caspases; Cell Proliferation; Chromans; Colonic Neoplasms; Dose-Response Relationship, Drug; Humans; Ligands; PPAR gamma; Proto-Oncogene Proteins c-bcl-2; Thiazolidinediones; Troglitazone; Tumor Cells, Cultured; 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