Every once in a while I review a natural substance supplement. This time its fucoidan, a complex sulfated polysaccharide (multi-sugar substance) found mainly in various species of brown seaweed. Known for about 40 years for multiple health-giving biological activities, fucoidan has been the subject of hundreds of research studies. Yet, my impression is that there is still much to be learned about this substance. In this post I attempt to clarify what is known about fucoidan and what is still to be learned.
The species of brown seaweed containiong fucoidan include kombu, limu moui, bladderwrack, wakame, mozuku, and hijiki. Also, variant forms of fucoidan have also been found in animal species, including the sea cucumber. Seaweed containing fucoidan have traditionally been consumed in places like Okinawa,Hawaii andTonga, locations known for the health and longevity of their populations. It is interesting that much of the research on fucoidan appears to have been done in Asia. Of the hundreds of publications on fucoidan, I can cite only a small sample of representative ones here.
From a web page of the Sloan Kettering Memorial Cancer Center:
“Clinical Summary: Fucoidan is a sulfated polysaccharide found in the cell walls of many species of Brown seaweed. Preliminary data show that fucoidan has antitumor and antiangiogenic (2) (3) (4) (5) (6) (7) effects in vitro. These effects are brought about by stimulating natural killer cells and by down regulating AP-I involved in cellular proliferation. Fucoidan also exhibited neuroprotective effects (11) (12), but human data is lacking. In other studies, fucoidan demonstrated anticoagulant (8) (9) and antithrombotic (10) activities, and can have additive effects when taken with anticoagulants.”
“Mechanism of Action: Fucoidan has been shown to inhibit metastasis by preventing adhesion of tumor cells to the extracellular matrix. This is achieved by blocking the fibronectin cell-binding domain, necessary for formation of adhesion complexes (4). Fucoidan was also shown to induce apoptosis of human T-cell leukemia virus type I (HTLV-1) that causes Adult T-cell leukemia. It does so by inactivating NF-kB that regulates antiapoptotic proteins. It suppresses AP-I, a transcription factor involved in cellular proliferation and transformation (3). An vitro study showed that Fucoidan can suppress angiogenesis induced by Sarcoma 180 cells in mice (5). Fucoidan has immunomodulating effects and enhanced the activity of NK cells, which play a crucial role in mediating tumor cell death (2). The neuroprotective effects of fucoidan are attributed to its ability to suppress tumor necrosis factor-alpha (TNF-alpha)- and interferon-gamma (IFN-gamma)-induced NO production in C6 glioma cells (11) and to its antioxidative effects (12).”
Fucoidan and cancers
The 2005 paper Fucoidan extracted from Cladosiphon okamuranus Tokida induces apoptosis of human T-cell leukemia virus type 1-infected T-cell lines and primary adult T-cell leukemia cells is a cell and mouse-level study. “Further analysis showed that fucoidan inactivated NF-kappaB and activator protein-1 and inhibited NF-kappaB-inducible chemokine, C-C chemokine ligand 5 (regulated on activation, normal T expressed and secreted) production, and homotypic cell-cell adhesion of HTLV-1-infected T-cell lines. In vivo use of fucoidan resulted in partial inhibition of growth of tumors of an HTLV-1-infected T-cell line transplanted subcutaneously in severe combined immune deficient mice. Our results indicate that fucoidan is a potentially useful therapeutic agent for patients with ATL.”.
The 2009 paper Inhibitory effect of fucoidan on Huh7 hepatoma cells through downregulation of CXCL12 described yet-another cell-level study. “The aim of this study is to assess whether fucoidan — exerts antitumor activity toward Huh7 hepatoma cells. According to 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, fucoidan inhibited the growth of Huh7 cells and HepG2 cells in a dose-dependent manner, with a 50% inhibition of cell growth (IC50) of 2.0 and 4.0 mg/ml, respectively.”
The 2009 paper Apoptosis inducing activity of fucoidan in HCT-15 colon carcinoma cells describes a pre-clinical study on colon cancer cells. “These findings provide evidence demonstrating that the pro-apoptotic effect of fucoidan is mediated through the activation of ERK, p38 and the blocking of the PI3K/Akt signal pathway in HCT-15 cells. These data support the hypothesis that fucoidan may have potential in colon cancer treatment.”
The 2009 paper Fucoidan induces apoptosis through activation of caspase-8 on human breast cancer MCF-7 cells describes another cell-level study. “ — we investigated the effect of fucoidan on the induction of apoptosis in human breast cancer MCF-7 cells. Our data demonstrated that fucoidan reduced the viable cell number of MCF-7 cells in a dose- and time-dependent manner. In contrast, fucoidan did not affect the viable cell number of normal human mammary epithelial cells. Results from the apoptosis assay demonstrated that fucoidan induced internucleosomal DNA fragmentation, chromatin condensation, activation of caspase-7, -8, and -9, and cleavage of poly(ADP ribose) polymerase.” Also see Intracellular signaling in the induction of apoptosis in a human breast cancer cell line by water extract of Mekabu
The 2009 paper Fucoidan-Vitamin C complex suppresses tumor invasion through the basement membrane, with scarce injuries to normal or tumor cells, via decreases in oxidative stress and matrix metalloproteinases, describes yet-another cell level study, this time involving fucoidan in combination with vitamin C. “Invasion of human fibrosarcoma cells HT-1080 through the basement membrane was repressed by Fucdn-VC-IB of non-cytotoxic concentrations without significant inhibition to human skin dermal fibroblasts DUMS-16 cells. Fucdn-VC-IB suppressed the invasiveness-related gelatinases MMP-2/9, and diminished reactive oxygen species inside the cytoplasm around the nucleus, in HT-1080 cells as shown by electrophoretic zymography and the redox indicator NBT assay, respectively. Thus Fucdn-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.”
The 2007 paper Antitumor and antimetastatic activity of fucoidan, a sulfated polysaccharide isolated from the Okhotsk Sea Fucus evanescens brown alga describes a mouse-based study. “Antitumor and antimetastatic activities of fucoidan, a sulfated polysaccharide isolated from Fucus evanescens (brown alga in Okhotsk sea), was studied in C57Bl/6 mice with transplanted Lewis lung adenocarcinoma. Fucoidan after single and repeated administration in a dose of 10 mg/kg produced moderate antitumor and antimetastatic effects and potentiated the antimetastatic, but not antitumor activities of cyclophosphamide. Fucoidan in a dose of 25 mg/kg potentiated the toxic effect of cyclophosphamide.”
Fucoidan, neurogenesis and neurological diseases
A 2010 Japanese paper Proliferative effects on neural stem/progenitor cells of a sulfated polysaccharide purified from the sea cucumber Stichopus japonicus suggests the interesting result that fucoidan can promote neurogenesis from neural stem progenitor cells. “Our results showed that HS (haishen, a highly sulfated fucoidan) alone increased NSPC viability in a dose-dependent manner. Moreover, HS acted synergistically with fibroblast growth factor-2 (FGF-2) but not epidermal growth factor (EGF) to enhance the proliferation of NSPCs. Finally, HS did not induce apoptosis of NSPCs. Our findings suggest that HS can serve as an adjuvant for promoting the proliferation of NSPCs.” Again, this is a cell-level study.
The 2009 publication Suppression of iNOS expression by fucoidan is mediated by regulation of p38 MAPK, JAK/STAT, AP-1 and IRF-1, and depends on up-regulation of scavenger receptor B1 expression in TNF-alpha- and IFN-gamma-stimulated C6 glioma cells is quite technical but interesting. “In neurodegenerative disorders, activated glial cells overproduce nitric oxide (NO), which causes neurotoxicity. Inducible NO synthase (iNOS) is a potential therapeutic target in neurodegenerative diseases. Here, we examined the action of fucoidan, a high-molecular-weight sulfated polysaccharide, on tumor necrosis factor-alpha (TNF-alpha)- and interferon-gamma (IFN-gamma)-induced NO production in C6 glioma cells. Fucoidan suppressed TNF-alpha- and IFN-gamma-induced NO production and iNOS expression. In addition, fucoidan inhibited TNF-alpha- and IFN-gamma-induced AP-1, IRF-1, JAK/STAT and p38 mitogen-activated protein kinase (MAPK) activation and induced scavenger receptor B1 (SR-B1) expression. — The present results also suggest that fucoidan could be a potential therapeutic agent for treating inflammatory-related neuronal injury in neurological disorders.”
Fucoidan and Alzheimer’s disease
Fucoidan could conceivably play a role in the treatment of Alzheimer’s disease, as suggested by the paper Functional and physical interactions between Formyl-Peptide-Receptors and Scavenger Receptor MARCO and their involvement in Amyloid beta 1-42 (Abeta1-42)-induced signal transduction in Glial Cells. “ — we have demonstrated a functional interaction between FPRL1 and scavenger receptors in fucoidan-mediated signalling by ERK1/2 phosphorylation and cAMP level measurement. In addition, co-immunoprecipitation data and fluorescence microscopy measurements revealed a physical interaction between FPR, FPRL1 and MARCO. These results suggest that FPRL1 plays a pivotal role for Abeta1-42-induced signal transduction in glial cells and the interaction with MARCO (which is promoted by fuciodan)could explain the broad ligand spectrum of formyl peptide receptors.” Again, this is a cell-level study.
The 2005publication Fucoidan inhibits cellular and neurotoxic effects of Î²-amyloid (AÎ²) in rat cholinergic basal forebrain neurons reports on a cell-level study. The publication states “Fucoidan also attenuated AÎ²-induced down-regulation of phosphorylated protein kinase C. AÎ²1âˆ’42-induced generation of reactive oxygen species was blocked by prior exposure of cultures to Fucoidan. Furthermore, AÎ² activation of caspases 9 and 3, which are signaling pathways implicated in apoptotic cell death, is blocked by pretreatment of cultures with Fucoidan. These results show that Fucoidan is able to block AÎ²-induced reduction in whole-cell currents in basal forebrain neurons and has neuroprotective effects against AÎ²-induced neurotoxicity in basal forebrain neuronal cultures.”
Fucoidan and Parkinson’s disease
The 2009 publication Fucoidan protects against dopaminergic neuron death in vivo and in vitro concludes “– we found that fucoidan inhibited MPTP-induced lipid peroxidation and reduction of antioxidant enzyme activity. In addition, pre-treatment with fucoidan significantly protected against MPP(+)-induced damage in MN9D cells. Taken together, these findings suggest that fucoidan has protective effect in MPTP-induced neurotoxicity in this model of Parkinson’s disease via its antioxidative activity.”
Fucoidan and herpes simplex
The 2008 study Defensive effects of a fucoidan from brown alga Undaria pinnatifida against herpes simplex virus infection reports “Fucoidan, — was previously shown to be a potent inhibitor of the in vitro replication of herpes simplex virus type 1 (HSV-1). HSV-1 is a member of herpes viruses that cause infections ranging from trivial mucosal ulcers to life-threatening disorders in immunocompromised hosts. — The production of neutralizing antibodies in the mice inoculated with HSV-1 was significantly promoted during the oral administration of the fucoidan for 3 weeks. These results suggested that oral intake of the fucoidan might take the protective effects through direct inhibition of viral replication and stimulation of both innate and adaptive immune defense functions.” Being a mouse study, the results are a step closer to having clinical relevancy than the results of cell-level studies such as cited above.
Clinical trials related to fucoidan
· A pilot clinical trial testing fucoidan as an oral anti-coagulant was reported last year Pilot clinical study to evaluate the anticoagulant activity of fucoidan. The outcome was negative. “Thus, fucoidan in the form used in this study does not seem to have an oral anticoagulant activity, but it has a very strong in-vitro anticoagulant activity.”
· A tiny and highly specialized clinical trial is reported in the publication Fucoidan ingestion increases the expression of CXCR4 on human CD34+ cells. The conlusion was “Oral fucoidan significantly amplified the CXCR4+ HPC (hematopoietic progenitor stem cells) population. The ability to mobilize HPC using sulfated polysaccharides and mobilize more HPC with high levels of CXCR4 could be clinically valuable.”·
· There is a Phase 1 clinical trial now in the recruiting stage Phase 1 Dosing Study of BAX 513 in Healthy Volunteers. Bax 513 is a fucoidan extract of Laminaria japonica. “A Phase 1 Study to Evaluate the Effects of BAX 513 on Hemostatic Parameters in Healthy Volunteers.” This is possibly the initial clinical trial in a series of them sponsored by big pharma companies
My take on fucoidan
· Based on cell-level and some mouse studies the substance appears to have possible therapeutic potential in many dimensions. Fucoidan has only recently become the subject of clinical investigations, however. So, despite the long-familiarity with the substance its utility as a human therapy remains largely unexplored.
· As conventional drug-discovery approaches become less productive, fucoidan is one of the natural substances pharmaceutical companies are starting to investigate. We may expect soon to see clinical trials of proprietary fucoidan compounds for specific disease indications.
· There appears to be an active market for fucoidan supplements with many sellers(ref). As of this moment, however, I am unclear whether or not fucoidan belongs in an anti-aging supplement regimen.
I expect we will be hearing a lot more about fucoidan as time progresses
What remarkable post! Fucoidan has only recently become the subject of clinical investigations, however. So, despite the long-familiarity with the substance its utility as a human therapy remains largely unexplored.
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