FUCOIDAN/CANCER RESEARCH abstracts FROM www.pubmed.gov
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1. Biol Pharm Bull. 2009 Oct;32(10):1760-4. Apoptosis inducing activity of fucoidan in HCT-15 colon carcinoma cells. Hyun JH, Kim SC, Kang JI, Kim MK, Boo HJ, Kwon JM, Koh YS, Hyun JW, Park DB, Yoo ES, Kang HK. School of Medicine, Institute of Medical Sciences, Jeju National University,South Kore. The anti tumor activity of fucoidan from Fucus vesiculosus was investigated in human colon carcinoma cells. The crude fucoidan, a polysaccharide composed predominantly of sulfated fucose, markedly inhibited the growth of HCT-15 cells(human colon carcinoma cells). After HCT-15 cells were treated with fucoidan,several apoptotic events such as DNA fragmentation, chromatin condensation andincrease of the population of sub-G1 hypodiploid cells were observed. In themechanism of fucoidan-induced apoptosis, we examined changes in Bcl-2 and Baxprotein expression levels and activation of caspases. Fucoidan decreased Bcl-2expression, whereas the expression of Bax was increased in a time-dependentmanner compared to the control. In addition, the active forms of caspase-9 andcaspase-3 were increased, and the cleavage of poly(ADP-ribose) polymerase (PARP),a vital substrate of effector caspase, was observed. Furthermore, the inductionof apoptosis was also accompanied by a strong activation of extracellularsignal-regulated kinase (ERK) and p38 kinase and an inactivation ofphosphatidylinositol 3-kinase (PI3K)/Akt in a time-dependent manner. Thesefindings provide evidence demonstrating that the pro-apoptotic effect of fucoidanis mediated through the activation of ERK, p38 and the blocking of the PI3K/Aktsignal pathway in HCT-15 cells. These data support the hypothesis that fucoidan may have potential in colon cancer treatment.
2. Int J Oncol. 2009 Nov;35(5):1183-9. Fucoidan-Vitamin C complex suppresses tumor invasion through the basementmembrane, with scarce injuries to normal or tumor cells, via decreases inoxidative stress and matrix metalloproteinases. Saitoh Y, Nagai Y, Miwa N. Cell-Death Control BioTechnology Laboratory, Faculty of Life and EnvironmentalSciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023,Japan. Fucoidan (Fucdn) and vitamin C (VC) were saturatedly dissolved in water andlyophilized and thoroughly ethanol-rinsed until no detection for supernatantvitamin C to form the Fucdn-VC (1:0.23 wt/wt) inclusion body (Fucdn-VC-IB).Fucdn-VC-IB increased not only VC-stabilizing at 37 degrees C, but alsohydroxyl-radical scavenging as shown by ESR/spin-trap method, more markedly than a mere mixture of Fucdn:VC (1:0.23 wt/wt). Invasion of human fibrosarcoma cellsHT-1080 through the basement membrane was repressed by Fucdn-VC-IB ofnon-cytotoxic concentrations without significant inhibition to human skin dermal fibroblasts DUMS-16 cells. Fucdn-VC-IB suppressed the invasiveness-relatedgelatinases MMP-2/9, and diminished reactive oxygen species inside the cytoplasm around the nucleus, in HT-1080 cells as shown by electrophoretic zymography andthe redox indicator NBT assay, respectively. Thus Fucoidan-VC-IB markedly exhibits antioxidant and MMP-suppressing activities and preferentially inhibited tumor invasion without cytotoxicity to normal cells, and is suggested as a potent tumor-invasion suppressor.
3. J Agric Food Chem. 2009 Sep 23;57(18):8677-82. Fucoidan induces apoptosis through activation of caspase-8 on human breast cancerMCF-7 cells. Yamasaki-Miyamoto Y, Yamasaki M, Tachibana H, Yamada K. Laboratory of Food Chemistry, Division of Applied Biological Chemistry,Department of Bioscience and Biotechnology, Faculty of Agriculture, KyushuUniversity, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.firstname.lastname@example.org Fucoidan is an active component of seaweed that has been shown to inhibitproliferation and induce apoptotic cell death in several tumor cells. However,the detailed mechanisms underlying this process have not yet been elucidated. In the present report, we investigated the effect of fucoidan on the induction ofapoptosis in human breast cancer MCF-7 cells. Our data demonstrated that fucoidanreduced the viable cell number of MCF-7 cells in a dose- and time-dependentmanner. In contrast, fucoidan did not affect the viable cell number of normalhuman mammary epithelial cells. Results from the apoptosis assay demonstratedthat fucoidan induced internucleosomal DNA fragmentation, chromatin condensation,activation of caspase-7, -8, and -9, and cleavage of poly(ADP ribose) polymerase.Furthermore, expression of Bid was decreased, whereas truncated Bid was increasedby fucoidan treatment. There was also a decline in cytosolic Bax and a strikingincrease of cytosolic cytochrome c. Caspase-8-specific inhibitor, z-ITED-fmk,canceled the cytotoxicity of fucoidan, activation of caspase-7, -8, and -9, and aseries of changes in Bax, Bid, and cytochrome c. However, caspase-9-specificinhibitor exerted a moderate inhibitory effect on the cytotoxicity of fucoidan.These data indicated that fucoidan could induce apoptotic cell death through acaspase-8-dependent pathway in MCF-7 cells.
4. Anticancer Res. 2009 Apr;29(4):1211-7. Effect of fucoidan on the biotinidase kinetics in human hepatocellular carcinoma. Hayakawa K, Nagamine T. 3-35-31 Taishido, Setagaya-ku, Tokyo 157-8535, Japan. email@example.com BACKGROUND: Hepatocellular carcinoma (HCC) is difficult to treat with anticancer drugs. Therefore, development of new drugs for HCC is required. MATERIALS ANDMETHODS: The livers of 14 hepatoma patients accompanied by hepatitis B (2 cases) and hepatitis C (12 cases) were used. The biotinidase kinetics of HCC tissueswere compared to those of the adjacent liver tissues of 13 liver cirrhosis (LC)and 1 chronic active hepatitis (CAH). RESULTS: The Kip (the inhibition constantby biotin) of HCC tissues were consistently higher than those of LC (plus CAH)tissues: the Kip was 450+/-231 micromol/l in HCC tissues and 240+/-111 micromol/lin LC (plus CAH) tissues, p<0.001. This increase of Kip is considered to be dueto an increase of biotin repulsion by biotinidase in the HCC tissues. Fucoidan, asulfated poly-fucose, was found to decrease the Kip of biotinidase in HCCtissues, and conversely to increase it in LC tissues. Fucoidan was also found to decrease the Kip of the hepatoma HuH-6 cells. CONCLUSION: These findings suggest that fucoidan has a potential therapeutic effect on HCC.
5. Nutr Cancer. 2009;61(3):340-7. Inhibitory effect of fucoidan on Huh7 hepatoma cells through downregulation ofCXCL12. Nagamine T, Hayakawa K, Kusakabe T, Takada H, Nakazato K, Hisanaga E, Iha M. School of Health Science, Gunma University, 3-39-15 Showamachi, Maebashi, Gunma371-8514, Japan. firstname.lastname@example.org The aim of this study is to assess whether fucoidan modulates the expression ofchemokine ligand 12 (CXCL12)/chemokine receptor 4 (CXCR4) and exerts antitumoractivity toward Huh7 hepatoma cells. According to3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays,fucoidan inhibited the growth of Huh7 cells and HepG2 cells in a dose-dependentmanner, with a 50% inhibition of cell growth (IC50) of 2.0 and 4.0 mg/ml,respectively. alpha-fetoprotein levels in medium collected from fucoidan-treated cells were significantly decreased in Huh7 cells but not in HepG2 cells. Western blotting revealed that the amount of alpha-fetoprotein was decreased by 1.0 mg/mlof fucoidan in Huh7 cells, whereas it was unchanged in HepG2 cells. In Huh7cells, CXCL12 mRNA expression was significantly downregulated by 1.0 mg/ml offucoidan, whereas CXCR4 mRNA expression was unchanged by fucoidan. CXCL12 andCXCR4 mRNA were barely expressed in HepG2 cells. In addition, 1.0 mg/ml offucoidan mildly arrested the cell cycle and induced apoptosis in Huh7 cells. The findings suggest that fucoidan exhibits anti tumor activity toward Huh7 cells through the down regulation of CXCL12 expression.
6. Int J Biol Macromol. 2008 Dec;43(5):433-7. Epub 2008 Aug 27. Effects of molecular weight and hydrolysis conditions on anticancer activity offucoidans from sporophyll of Undaria pinnatifida. Yang C, Chung D, Shin IS, Lee H, Kim J, Lee Y, You S. Department of Marine Food Science and Technology, Kangnung National University,Gangneung, Gangwon 210-702, Republic of Korea. Hydrolyzed fucoidans, from sporophyll of Undaria pinnatifida, were used todetermine the effects of molecular weight (Mw) and hydrolysis conditions oncancer cell growth. Native fucoidans showed anticancer activity of 37.6%. Whenhydrolyzed in boiling water with HCl for 5 min, fucoidans (Mw = 490 kDa)significantly increased anticancer activity to 75.9%. However, fucoidanshydrolyzed in a microwave oven showed little improvement of anticancer activityand even exhibited the inhibition activity below 30% when treated more than 90s. This suggests that anticancer activity of fucoidans could be significantly enhanced by lowering their Mw only when they are depolymerized by mild condition.
7. Int Immunopharmacol. 2008 Dec 20;8(13-14):1754-60. Epub 2008 Sep 8. Fucoidan stimulation induces a functional maturation of human monocyte-deriveddendritic cells. Yang M, Ma C, Sun J, Shao Q, Gao W, Zhang Y, Li Z, Xie Q, Dong Z, Qu X. Institute of Basic Medical Sciences, Qilu Hospital, Shandong University, Jinan,250012, Shandong, People’s Republic of China. Fucoidan is a complex sulfated polysaccharide with a wide variety of biologicalactivities for modulating immune cell functions. However, the effects of fucoidanon maturation process and activation of human monocyte-derived dendritic cells(DCs) remain to be elucidated. The present study demonstrated that the level ofspecial marks and polarization phenotype of DCs was altered by fucoidan. Humanmonocytes were cultured with GM-CSF and IL-4 for 5 days followed by another 2days in the presence of fucoidan or LPS. Then DCs were harvested on day 7 andwere examined using functional assays. We demonstrated that fucoidan up-regulatedthe expression of HLA-DR and co-stimulatory molecules of DCs. However theendocytic activity was impaired markedly. Fucoidan induces their Th1-promotingtumor necrosis factor alpha (TNF-alpha) and interleukin-12 (IL-12) secretion, andenhances their allostimulatory capacity. In an allogeneic MLR assay, DCs treated with fucoidan were potent in the secretion of IL-12p70, TNF-alpha and IFN-gamma. Naive T cells stimulated by fucoidan-treated DCs differentiated towards a helper T cell type 1 (Th1) response depending on IL-12 secretion. These results suggest that fucoidan may induce immature DCs maturation and drive their differentiation towards a Th1-polarizing phenotype. Moreover, our data suggest that DCs appear tobe a potential target for the immunomodulatory capacity of fucoidan and fucoidan may be used on DC-based vaccines for cancer immunotherapy.
8. Am J Physiol Lung Cell Mol Physiol. 2008 Jun;294(6):L1137-48. Epub 2008 Apr 4. Impact of the FcgammaII-receptor on quartz uptake and inflammatory response byalveolar macrophages. Haberzettl P, Schins RP, Höhr D, Wilhelmi V, Borm PJ, Albrecht C. Particle Research, Institut für Umweltmedizinische Forschung at the HeinrichHeine University, Auf’m Hennekamp 50, 40225 Düsseldorf, Germany. The inflammatory response following particle inhalation is described as a keyevent in the development of lung diseases, e.g., fibrosis and cancer. Theessential role of alveolar macrophages (AM) in the pathogenicity of particlesthrough their functions in lung clearance and mediation of inflammation is wellknown. However, the molecular mechanisms and direct consequences of particleuptake are still unclear. Inhibition of different classic phagocytosis receptors by flow cytometry shows a reduction of the dose-dependent quartz particle (DQ12) uptake in the rat AM cell line NR8383. Thereby the strongest inhibitory effectwas observed by blocking the FcgammaII-receptor (FcgammaII-R). Fluorescenceimmunocytochemistry, demonstrating FcgammaII-R clustering at particle bindingsites as well as transmission electron microscopy, visualizing zipperingmechanism-like morphological changes, confirmed the role of the FcgammaII-R inDQ12 phagocytosis. FcgammaII-R participation in DQ12 uptake was furtherstrengthened by the quartz-induced activation of the Src-kinase Lyn, thephospho-tyrosine kinases Syk (spleen tyrosine kinase) and PI3K(phosphatidylinositol 3-kinase), as shown by Western blotting. Activation of the small GTPases Rac1 and Cdc42, shown by immunoprecipitation, as well as inhibitionof tyrosine kinases, GTPases, or Rac1 provided further support for the role ofthe FcgammaII-R. Consistent with the uptake results, FcgammaII-R activation with its specific ligand caused a similar generation of reactive oxygen species andTNF-alpha release as observed after treatment with DQ12. In conclusion, our results indicate a major role of FcgammaII-R and its downstream signaling cascadein the phagocytosis of quartz particles in AM as well as in the associated generation and release of inflammatory mediators.
9. Food Chem Toxicol. 2008 May;46(5):1793-800. Epub 2008 Jan 26. Inhibitory effects of fucoidan on activation of epidermal growth factor receptor and cell transformation in JB6 Cl41 cells. Lee NY, Ermakova SP, Zvyagintseva TN, Kang KW, Dong Z, Choi HS. College of Pharmacy, Chosun University, Gwangju, South Korea. Algal fucoidan is a marine sulfated polysaccharide with a wide variety ofbiological activities including anti-thrombotic, anti-inflammatory, andanti-tumor activities. In this study, we tested the hypothesis that fucoidan may suppress neoplastic cell transformation by inhibiting the phosphorylation ofepidermal growth factor receptor (EGFR) in mouse epidermal JB6 Cl41 cells. Ourresults provided the first evidence that fucoidan from Laminaria guryanovaeexerted a potent inhibitory effect on EGF-induced phosphorylation of EGFR.Consistent with its inhibitory action on phosphorylation of EGFR, fucoidanclearly suppressed the phosphorylation of extracellular signal-regulated kinaseor c-jun N-terminal kinases induced by EGF. Moreover, EGF-induced the c-fos andc-jun transcriptional activities were inhibited by fucoidan, resulting tosuppressing of activator protein-1 (AP-1) activity and cell transformationinduced by EGF. Taken together, these results indicate that fucoidan might exert chemopreventive effects through the inhibition of phosphorylation of the EGFR. 10. Mol Carcinog. 2008 Aug;47(8):629-37. Fucoidan from Laminaria cichorioides inhibits AP-1 transactivation and celltransformation in the mouse epidermal JB6 cells. Lee NY, Ermakova SP, Choi HK, Kusaykin MI, Shevchenko NM, Zvyagintseva TN, ChoiHS. College of Pharmacy, Chosun University, Gwangju, South Korea. Fucoidan, a sulfated polysaccharide extracted from brown seaweeds, hasanticoagulant and antithrombotic activities. Unlike heparine, fucoidan is knownto exhibit anticarcinogenic activities. However, the underlying molecularmechanisms of the chemopreventive activities of fucoidan are not understood. Herewe report that fucoidan from Laminaria cichorioides inhibited the epidermalgrowth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA)-inducedneoplastic cell transformation, but had less cytotoxic effects on JB6 mouseepidermal cells. The EGF-induced phosphorylation of extracellularsignal-regulated kinases 1/2 and c-Jun N-terminal kinases, and c-Jun wasinhibited by fucoidan, resulting from the inhibition of phosphorylation ofepidermal growth factor receptor (EGFR). Fucoidan dose-dependently attenuated thec-fos or c-jun transcriptional activity, and thereby inhibited the associatedactivator protein-1 (AP-1) transactivation activity. In vitro binding assayrevealed that fucoidan directly interacted with EGF, suggested that antitumorpromoting effect of fucoidan might be due to preventing the binding of EGF to itscell surface receptor (EGFR). These findings are the first to reveal a molecular basis for the anticarcinogenic action of fucoidan and may partially account for the reported chemo preventive effects of brown seaweeds. (c) 2008 Wiley-Liss, Inc.
11. Blood. 2008 Apr 15;111(8):4126-36. Epub 2008 Feb 13. Sulfated polysaccharides identified as inducers of neuropilin-1 internalizationand functional inhibition of VEGF165 and semaphorin3A. Narazaki M, Segarra M, Tosato G. The Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1907, USA. Neuropilin-1 (NRP1) and NRP2 are cell surface receptors shared by class 3semaphorins and vascular endothelial growth factor (VEGF). Ligand interactionwith NRPs selects the specific signal transducer, plexins for semaphorins or VEGFreceptors for VEGF, and promotes NRP internalization, which effectively shutsdown receptor-mediated signaling by a second ligand. Here, we show that thesulfated polysaccharides dextran sulfate and fucoidan, but not others, reduceendothelial cell-surface levels of NRP1, NRP2, and to a lesser extent VEGFR-1 andVEGFR-2, and block the binding and in vitro function of semaphorin3A andVEGF(165). Administration of fucoidan to mice reduces VEGF(165)-inducedangiogenesis and tumor neovascularization in vivo. We find that dextran sulfateand fucoidan can bridge the extracellular domain of NRP1 to that of the scavengerreceptor expressed by endothelial cells I (SREC-I), and induce NRP1 and SREC-Icoordinate internalization and trafficking to the lysosomes. Overexpression ofSREC-I in SREC-I-negative cells specifically reduces cell-surface levels of NRP1,indicating that SREC-I mediates NRP1 internalization. These results demonstrate that engineered receptor internalization is an effective strategy for reducing levels and function of cell-surface receptors, and identify certain sulfated polysaccharides as “internalization inducers.”
12. Bull Exp Biol Med. 2007 Jun;143(6):730-2. Antitumor and antimetastatic activity of fucoidan, a sulfated polysaccharideisolated from the Okhotsk Sea Fucus evanescens brown alga. [Article in English, Russian] Alekseyenko TV, Zhanayeva SY, Venediktova AA, Zvyagintseva TN, Kuznetsova TA,Besednova NN, Korolenko TA. Institute of Physiology, Siberian Division of Russian Academy of MedicalSciences, Novosibirsk. Antitumor and antimetastatic activities of fucoidan, a sulfated polysaccharideisolated from Fucus evanescens (brown alga in Okhotsk sea), was studied inC57Bl/6 mice with transplanted Lewis lung adenocarcinoma. Fucoidan after singleand repeated administration in a dose of 10 mg/kg produced moderate antitumor andantimetastatic effects and potentiated the antimetastatic, but not antitumoractivities of cyclophosphamide. Fucoidan in a dose of 25 mg/kg potentiated the toxic effect of cyclophosphamide.
13. Yakugaku Zasshi. 2008 Jan;128(1):61-79. [Studies on evaluation of natural products for antiviral effects and theirapplications] [Article in Japanese] Hayashi T. Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Sugitani, Toyama City, Japan. email@example.com In the search for novel antiviral molecules from natural products, we havediscovered various antiviral molecules with characteristic mechanisms of action. Scopadulciol (SDC), isolated from the tropical medicinal plant Scoparia dulcisL., showed stimulatory effects on the antiviral potency of acyclovir (ACV) organciclovir (GCV). This effect of SDC was exerted via the activation of viralthymidine kinase (HSV-1 TK) and, as a result, an increase in the cellularconcentration of the active form of ACV/GCV, i.e., the triphosphate of ACV orGCV. On the basis of these experimental results, cancer gene therapy using theHSV-1 tk gene and ACV/GCV together with SDC was found to be effective insuppressing the growth of cancer cells in animals. Acidic polysaccharides such ascalcium spirulan (Ca-SP) from Spirulina platensis, nostoflan from Nostocflagelliforme, and a fucoidan from the sporophyll of Undaria pinnatifida (mekabu fucoidan) were also found to be potent inhibitors against several envelopedviruses. Their antiviral potency was dependent on molecular weight and content ofthe sulfate or carboxyl group as well as counterion species chelating withsulfate groups, indicating the importance of the three-dimensional structure ofthe molecules. In addition, unlike dextran sulfate, Ca-SP was shown to target notonly viral absorption/penetration stages but also some replication stages ofprogeny viruses after penetration into cells. When mekabu fucoidan or nostoflan was administered with oseltamivir phosphate, their synergistic antiviral effects on influenza A virus were confirmed in vitro as well as in vivo.
14. Exp Oncol. 2007 Sep;29(3):181-5. Sensitization of human malignant lymphoid cells to etoposide by fucoidan, a brownseaweed polysaccharide. Philchenkov A, Zavelevich M, Imbs T, Zvyagintseva T, Zaporozhets T. R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology,National Academy of Sciences of Ukraine, 03022 Kyiv, Ukraine.firstname.lastname@example.org The search for the substances sensitizing cancer cells to apoptosis induction by chemotherapeutic agents is a task of high importance in the modern strategy ofanticancer therapy. THE AIM of the study was to investigate the apoptogenic andapoptosis-modulating activities of fucoidan (sulfated polysaccharide) isolatedfrom far-eastern brown seaweeds Fucus evanescens in two human malignant lymphoid cell lines, MT-4 and Namalwa. METHODS: Apoptosis was assessed morphologically andquantified by flow cytometry analysis of cells stained with propidium iodide.Caspase-3 activation was assayed by flow cytometry with the aid of labeledmonoclonal antibodies. RESULTS: The fucoidan at 500 microg/ml was not cytotoxicin MT-4 or Namalwa cells even in the setting of long-term presence in culturemedium up to 14 days. Nevertheless, pretreatment of MT-4 but not Namalwa cellswith fucoidan followed by the exposure to DNA topoisomerase II inhibitoretoposide led to about two-fold increase in the relative apoptotic index ascompared with etoposide alone. Apoptosis enhancement of MT-4 cells by fucoidanwas not accompanied by further increase in the number of the cells with activeform of caspase-3. CONCLUSION: The present findings demonstrate for the firsttime that fucoidan enhances etoposide induced caspase-dependent cell deathpathway in MT-4 but not Namalwa cell line. The mechanisms of such enhancement do not seem to be related directly to caspase-3 activation.
15. Glycobiology. 2007 Oct;17(10):1094-103. Epub 2007 Aug 2. The binding of human betacellulin to heparin, heparan sulfate and relatedpolysaccharides. Mummery RS, Mulloy B, Rider CC. School of Biological Sciences, Royal Holloway University of London, Egham Hill,Egham, Surrey TW20 OEX, UK. Recombinant human betacellulin binds strongly to heparin, requiring of the order of 0.8 M NaCl for its elution from a heparin affinity matrix. This is in completecontrast to the prototypic member of its cytokine superfamily, epidermal growthfactor, which fails to bind to the column at physiological pH and strength. Weused a well-established heparin binding ELISA to demonstrate that fucoidan and a highly sulfated variant of heparan sulfate compete strongly for heparin binding. Low sulfated heparan sulfates and also chondroitin sulfates are weakercompetitors. Moreover, although competitive activity is reduced by selectivedesulfation, residual binding to extensively desulfated heparin remains. Evencarboxyl reduction followed by extensive desulfation does not completely removeactivity. We further demonstrate that both hyaluronic acid and the E. colicapsular polysaccharide K5, both of which are unsulfated polysaccharides withunbranched chains of alternating N-acetylglucosamine linked beta(1-4) toglucuronic acid, are also capable of a limited degree of competition withheparin. Heparin protects betacellulin from proteolysis by LysC, but K5polysaccharide does not. Betacellulin possesses a prominent cluster of basic residues, which is likely to constitute a binding site for sulfated polysaccharides, but the binding of nonsulfated polysaccharides may take place ata different site.
16. Exp Hematol. 2007 Jun;35(6):989-94. Fucoidan ingestion increases the expression of CXCR4 on human CD34+ cells. Irhimeh MR, Fitton JH, Lowenthal RM. Discipline of Medicine, Clinical School, University of Tasmania, Hobart,Australia. email@example.com OBJECTIVE: Transplantation of hematopoietic progenitor stem cells (HPC) is animportant treatment modality for a variety of neoplastic diseases. HPC collectionfor transplantation with granulocyte colony-stimulating factor may beunsuccessful in patients who have received prior chemotherapy or for otherreasons. Methods to improve mobilization of HPCs are required. Disruption of the interaction between the cell surface receptor CXCR4 and its ligand stromalderived factor-1 (SDF-1) is a mechanism for HPC release from the bone marrow intothe peripheral blood (PB). METHODS: We carried out a clinical trial to evaluatethe effects of ingestion of a fucoidan, galactofucan sulfate (a putative HPCmobilizing agent) on circulating CD34(+) cells, CXCR4 expression, and levels ofSDF-1, interferon gamma (IFN-gamma) and interleukin 12. RESULTS: Followingingestion of fucoidan, CD34(+) cells increased significantly in the PB from 1.64 to 1.84 cells/microL after 4 days. The proportion of CD34(+) cells that expressedCXCR4 increased from 45 to 90% after 12 days, the plasma level of SDF-1 increasedfrom 1978 to 2010 pg/mL, and IFN-gamma level increased from 9.04 to 9.89 pg/mL.CONCLUSION: Oral fucoidan significantly amplified the CXCR4(+) HPC population.The ability to mobilize HPC using sulfated polysaccharides and mobilize more HPC with high levels of CXCR4 could be clinically valuable.
17. Glycobiology. 2007 May;17(5):541-52. Epub 2007 Feb 12. A comparative study of the anti-inflammatory, anticoagulant, antiangiogenic, and antiadhesive activities of nine different fucoidans from brown seaweeds. Cumashi A, Ushakova NA, Preobrazhenskaya ME, D’Incecco A, Piccoli A, Totani L,Tinari N, Morozevich GE, Berman AE, Bilan MI, Usov AI, Ustyuzhanina NE, GrachevAA, Sanderson CJ, Kelly M, Rabinovich GA, Iacobelli S, Nifantiev NE; ConsorzioInteruniversitario Nazionale per la Bio-Oncologia, Italy. Department of Oncology and Neurosciences, University G. D’Annunzio Medical School& Foundation, 66013 Chieti, Italy, and Division of Immunogenetics, Hospital deClínicas José de San Martín, Buenos Aires, Argentina. The anti-inflammatory, antiangiogenic, anticoagulant, and antiadhesive propertiesof fucoidans obtained from nine species of brown algae were studied in order toexamine the influence of fucoidan origin and composition on their biologicalactivities. All fucoidans inhibited leucocyte recruitment in an inflammationmodel in rats, and neither the content of fucose and sulfate nor other structuralfeatures of their polysaccharide backbones significantly affected the efficacy offucoidans in this model. In vitro evaluation of P-selectin-mediated neutrophiladhesion to platelets under flow conditions revealed that only polysaccharidesfrom Laminaria saccharina, L. digitata, Fucus evanescens, F. serratus, F.distichus, F. spiralis, and Ascophyllum nodosum could serve as P-selectininhibitors. All fucoidans, except that from Cladosiphon okamuranus carryingsubstantial levels of 2-O-alpha-D-glucuronopyranosyl branches in the linear(1–>3)-linked poly-alpha-fucopyranoside chain, exhibited anticoagulant activity as measured by activated partial thromboplastin time whereas only fucoidans from L. saccharina, L. digitata, F. serratus, F. distichus, and F. evanescensdisplayed strong antithrombin activity in a platelet aggregation test. The lastfucoidans potently inhibited human umbilical vein endothelial cell (HUVEC)tubulogenesis in vitro and this property correlated with decreased levels ofplasminogen-activator inhibitor-1 in HUVEC supernatants, suggesting a possiblemechanism of fucoidan-induced inhibition of tubulogenesis. Finally, fucoidansfrom L. saccharina, L. digitata, F. serratus, F. distichus, and F. vesiculosusstrongly blocked MDA-MB-231 breast carcinoma cell adhesion to platelets, aneffect which might have critical implications in tumor metastasis. The datapresented herein provide a new rationale for the development of potential drugsfor thrombosis, inflammation, and tumor progression.
18. Thromb Haemost. 2006 Jan;95(1):1-2. Ways to bypass a blocked tenase complex. Tuddenham EG. PMID: 16543953 [PubMed – indexed for MEDLINE]
19. J Med Food. 2005 Winter;8(4):446-53. Immunomodulating activity of arabinogalactan and fucoidan in vitro. Choi EM, Kim AJ, Kim YO, Hwang JK. Department of Biotechnology & Bioproducts Research Center, Yonsei University,Seoul, South Korea. Many polysaccharides obtained from natural sources are considered to bebiological response modifiers and have been shown to enhance various immuneresponses. Here, we investigated the immunomodulating effects of arabinogalactan (AG) and fucoidan (FU) in vitro. Mouse spleen lymphocytes became cytotoxic totumor cells after culture with AG and FU at concentrations of 10-100 microg/mL.Also, AG and FU were mitogenic in spleen lymphocytes and peripheral macrophages. Macrophages treated with AG and FU (10-100 microg/mL) exhibited inducedtumoricidal activity and increased phagocytosis, lysosomal enzyme activity, andproduction of nitrite, H2O2, tumor necrosis factor (TNF)-alpha, and interleukin(IL)-6. However, AG and FU had little effect on the level of IL-1beta. Thus, the tumoricidal effect of AG- and FU-activated macrophages appeared to be mainlymediated by production of free radicals (NO and H2O2) and cytokines (TNF-alphaand IL-6). These data suggest that AG and FU are activators of lymphocytes andmacrophages. This property may contribute to their effectiveness in the immuno prevention of cancer.
20. Nutr Cancer. 2005;52(2):189-201. Fucoidan extracted from Cladosiphon okamuranus Tokida induces apoptosis of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cellleukemia cells. Haneji K, Matsuda T, Tomita M, Kawakami H, Ohshiro K, Uchihara JN, Masuda M,Takasu N, Tanaka Y, Ohta T, Mori N. Division of Molecular Virology and Oncology, Graduate School of Medicine,University of the Ryukyus, Nishihara, Okinawa, Japan. Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1(HTLV-1) and remains incurable. The highest endemic area of HTLV-1 carriers inJapan is located in Okinawa, and novel treatments are urgently needed in thisarea. We extracted fucoidan, a sulfated polysaccharide, from the brown seaweedCladosiphon okamuranus Tokida cultivated in Okinawa, Japan and examined itstumor-suppression activity against ATL. Fucoidan significantly inhibited thegrowth of peripheral blood mononuclear cells of ATL patients and HTLV-1-infected T-cell lines but not that of normal peripheral blood mononuclear cells. Fucoidan induced apoptosis of HTLV-1-infected T-cell lines mediated through downregulationof cellular inhibitor of apoptosis protein-2 and survivin and G1 phaseaccumulation through the downregulation of cyclin D2, c-myc, andhyperphosphorylated form of the retinoblastoma tumor suppressor protein. Further analysis showed that fucoidan inactivated NF-kappaB and activator protein-1 andinhibited NF-kappaB-inducible chemokine, C-C chemokine ligand 5 (regulated onactivation, normal T expressed and secreted) production, and homotypic cell-cell adhesion of HTLV-1-infected T-cell lines. In vivo use of fucoidan resulted inpartial inhibition of growth of tumors of an HTLV-1-infected T-cell linetransplanted subcutaneously in severe combined immune deficient mice. Our resultsindicate that fucoidan is a potentially useful therapeutic agent for patientswith ATL.