Monday, January 18, 2021

FUCOIDAN: Anti-Cancer Functions + Inhibitor of Covid-19?





By: Dr. Robert L. Bard & Adrian Barrios  (NY Cancer Resource Alliance writing team)

A natural health ingredient known as FUCOIDAN has joined our western fight against cancer  -native to the cold temperate seas of China, Japan, Korea. According to Memorial Sloan Kettering Cancer Center, "Fucoidan is a complex polysaccharide found in many species of brown seaweed (including Undaria pinnatifida and Cladosiphon okamuranus Tokida).... shown to slow blood clotting. Laboratory studies suggest that it can prevent the growth of cancer cells and has antiviral, neuroprotective, and immune-modulating effects."

In addition to its anticancer & anti-tumor components, Fucoidan has also shown effects as an antioxidant, anti-angiogenic, antiviral, and anticoagulant activities. [5]  These properties have captured the current interest of clinicians determined to produce treatment solutions for the complex symptoms of the CoronaVirus.  At the advent of public recognition of the drug REMDESEVIR (a widely popularized drug for its qualities as an immunomodulator), recent news headlines are highlighting major comparisons and competing statements with "the Seaweed extract to out-perform Remdesivir as a Covid inhibitor".  Also, Fucoidan has been compared to HEPARIN, an anticoagulant for its chemical composition of sulfated polysaccharide.

REMDESIVIR: Is recognized as the first approved drug to be effective against SARS-CoV-2. [8]
In a clinical study (on 8/6/2020) by The National Institute of Allergy and Infectious Diseases (NIAID)- a branch of the NIHtests for the efficacy of the antiviral Remdesivir + the interferon Beta-1a is underway a potential COVID-19 treatment.  "Laboratory studies suggest... type 1 interferon can inhibit SARS-CoV-2 and two closely related viruses, SARS-CoV and MERS-CoV. In addition, two small randomized controlled trials suggest that treatment with interferon beta may benefit patients with COVID-19." [6]


First isolated by Dr. Harvey Kylin in 1913 (Uppsala University, Swden), Fucoidan has been known to come from different species of brown algae and seaweed, carrying different biochemical properties[0] Fucoidan's bioactivity has been linked to its anti-cancer properties including the induction of inflammation through the immune system, oxidative stress and stem cell mobilization[1].

The anti-cancer property of fucoidan has been demonstrated in vivo and in vitro in different types of cancers. For the Immune System, Fucoidan has been recognized to increase the number of natural killer cells and increase in the number of cytotoxic T-cells. Tests/Trials of fucoidan's effects on dendritic cells showed that the stimulation of CTLs was more effective in fucoidan-treated DCs which exerted a high level of specific lysis of breast cancer cells [2]. In addition, Fucoidan has also been known to carry (immunomodulatory) protective effects against the side effects from chemotherapies or radiation.

Geographical distribution of Okinawa mozuku.
Anti-inflammation
Inflammation and immunity play important roles in the development of tumorigenesis [7]. Current epidemiological and preclinical results strongly support an anti-inflammatory approach to treating cancers. Several therapeutic agents targeting cancer-derived inflammatory responses and related signaling molecules, cytokines, transcription factors, and immune cells are being developed and tested [7.5]. Inflammation, cancer recurrence and cancer metastasis have a complicated relationship. Inflammatory responses play important roles in tumor development, including metastasis [9].

In mid-2018, an oral administration and absorption study of Mozuku fucoidan in 396 Japanese volunteers was performed. [10]. The results showed that fucoidan absorption in humans is extremely low; the fucoidan concentration after oral administration was approximately ten times higher in urine than in serum, confirming the intestinal absorption of Mozuku fucoidan in humans. The results indicated that volunteers living in Okinawa prefecture have the maximum value of urinary fucoidan, significantly higher estimated urinary excretion of fucoidan by place of residence, and significantly higher Mozuku fucoidan consumption habits compared with those living outside Okinawa prefecture. However, the biological mechanisms of fucoidan absorption across the intestinal tract need to be further investigated.






FROM THE SOURCE

This section is directly sourced from an interview with Dr. Yoshiyuki Miyazaki at the NPO Research Institute of Fucoidan in Fukuota, Japan.  Dr. Miyazaki received his PhD in Food Science and Biotechnology (2003) at Kyushu University.  He achieved a post-doctoral fellowship of JST, and then worked on basic research work on the immune regulation in infectious and allergic diseases at Saga University as associate professor (2004-2009). Since 2014, he started FUCOIDAN research on anti-cancer and immune regulatory effects to improve “Quality of Life” at NPO Research Institute of Fucoidan as chief researcher (2010-2011). After receiving a research fellowship (2014-2016), he assumed an associate professorship in the Laboratory of Bioactive Polysaccharide Analysis in Kyushu University where he performed research work on mechanisms in the regulation of intestinal immunity by fucoidan to enhance anti-tumor immunity (2016-present)



FUCOIDAN AND THE IMMUNE SYSTEM

Fucoidan is extracted using a special filtration membrane, and components with a molecular weight of 10,000 or less (impurities such as salts, heavy metals) are removed during the extraction process. As in the case of a research program from Keio University, synthesis of Fucoidan [1][2][3], is possible at the laboratory level, but has not yet been put to practical use.

We emphasize that the actual physiological action of Fucoidan is not "anti-cancer" that suppresses the growth of cancer cells with direct interaction, but "immune improvement" that is a host defense mechanism to prevent tumor growth. It is believed that Fucoidan activates the human body's natural immune mechanism that leads to the treatment of diseases that progress with a measurable decrease in immunity. I have studied on the mechanism of immune regulation by Fucoidan since 2010 as chief researcher in NPO Research Institute of Fucoidan, and now continuing in Laboratory of Bioactive Polysaccharide Analysis, Faculty of Agriculture in Kyushu University (2016. 4 - present, associate professor). Through 10 years of research, I have found unique and certain immuno-potentiating effects of Fucoidan. I hope that immune enhancement by Fucoidan may enhance the host resistance against SARS-CoV-2 and vaccine efficacy for Covid-19 treatment.

Fucoidan is not classified as a drug, therefore is not currently applied as a measurable treatment solution for the pandemic. (Development of vaccines for COVID-19 is desired to improve the current situation.) Fucoidan may, however be used as an effective supplement to immune enhancement in the vaccination.


EFFICACY & GLOBAL ACCEPTANCE

Some human trials have revealed useful physiological effects of Fucoidan improving medical treatment. However, in my opinion, there remains varied challenges in pharmaceutical approval of Fucoidan (due to the reasons described above)  unless mass-production of synthetic Fucoidan would be developed. Meanwhile, laboratory studies indicated success in synthesizing Fucoidan at the Keio University research program-- whereby the effects of oligofucosides, synthetic sulfated oligosaccharide with backbone structures of Fucoidan have been investigated on cancer cell growth [1][2] and influenza virus infection [3].

Currently, the scientific and medical communities have no conclusive evidence of therapeutic effects of Fucoidan on SARS-CoV-2. However, Fucoidan has been known to prevent dengue virus infection by direct interaction with viral envelope glycoprotein[4]. Furthermore, it was reported that Fucoidan possibly control influenza virus infection by augment immune responses, especially virus neutralizing antibody production[5]. In this context, we previously reported that Fucoidan derived from Undaria pinnatifida augmented immunoglobulin (IgA, IgG and IgM) production by mouse spleen lymphocytes[6]. So, we are believing that Fucoidan have sure physiological activities to reinforce vaccine efficacy.



ACTIVE COMPONENTS
Fucoidan is a natural ingredient with complex composition- whereby its pharmacological component is not a single chemical substance like a DRUG or MEDICINE. Fucoidan is a kind of polysaccharide, but similar polysaccharides have β-glucan derived from mushrooms (compounded in Umi-no-Shizuku). A purified β-glucan preparation named "Lentinan" has uniform composition and is approved as a drug for gastric cancer in Japan. In contrast, "Fucoidan" cannot be expected to have medicinal action by single component like β-glucan, so it is used as a naturally occurring SUPPLEMENT like Kampo rather than pharmaceuticals.

The source plant of Fucoidan is not only Undaria pinnatifida but also Cladosiphon okamuranus Tokida-  the most major species of Mozuku Fucoidan (Okinawa mozuku in Japanese name).
Physiological properties of Fucoidan has had extensive presence in the health and wellness communities, where scientific information is accessible in many articles- including Therapies from Fucoidan; Multifunctional Marine Polymers[7]   A protective effect of Fucoidan against side effects from chemotherapy with FOLFOX or FOLFIRI has been investigated in the following report; Fucoidan reduces the toxicities of chemotherapy for patients with unresectable advanced or recurrent colorectal cancer[8]


GEORGRAPHIC SOURCING
I believe Fucoidan is related to brown algae habitat and food culture. In Japan, it can be seen that seaweed has been used for health since ancient times, since there is a description in "本草和名:Honzo Wamyo", the oldest existing drug dictionary in Japan compiled around the year 900 AD. In Japan, where the country faces the sea, a food culture that incorporates seafood into the diet takes root, and it is thought that aquaculture of seaweeds and the research have advanced.

Seaweeds are classified into three groups, "red algae", "green algae" and "brown algae", and Fucoidan is a component contained only in brown algae. Other plants do not have Fucoidan.
Among the brown algae, only Fucoidan contained in Mozuku (Cladosiphon okamuranus Tokida), Mekabu (Undaria pinnatifida), and Gagomecomb (Kjellmaniella crassifolia) has the Japan Health Food Authorization (JHFA)[9] quality standards and can be certified as conforming.  The association conducts work that contributes to the health promotion of the Japanese nationals, such as collecting and spreading information on food with health claims and operating JHFA and other certifications.

According to reports, response of Fucoidan appears to affect a higher rate of residents of the sourced area (Japan) than any other part of the globe.  The research team at "Station Biologique de Roscoff", research and educational institute for marine biology and oceanography in France, reported that Japanese can decompose some kinds of polysaccharides contained in seaweed, because their enterobacteria (Bacteroides plebeius) took up gene for degrading enzyme from other marine microorganisms (published in British scientific journal "Nature" at April 8, 2010). Even within Japan, there are regional differences as with food culture, so I believe it is highly possible that there will be regional differences in the effects of Fucoidan around the world.


DOWNLOAD FUCOIDAN TRAINING MATERIALS from the Fucoidan Research Institute



References:
1) Systematic synthesis of sulfated oligofucosides and their effect on breast cancer MCF-7 cells (https://pubs.rsc.org/en/content/articlehtml/2014/cc/c4cc03544e)
2) Systematic synthesis of low-molecular weight Fucoidan derivatives and their effect on cancer cells (https://pubs.rsc.org/en/content/articlehtml/2015/ob/c5ob01634g)
3) Novel hemagglutinin-binding sulfated oligofucosides and their effect on influenza virus infection (https://pubs.rsc.org/en/content/articlehtml/2018/cc/c8cc03865a)
4) Structure and anti-dengue virus activity of sulfated polysaccharide from a marine alga (https://www.sciencedirect.com/science/article/pii/S0006291X08016562)
5) Supplementation of Elderly Japanese Men and Women with Fucoidan from Seaweed Increases Immune Responses to Seasonal Influenza Vaccination (https://academic.oup.com/jn/article/143/11/1794/4637681)
6) The enhancing effect of Fucoidan derived from Undaria pinnatifida on immunoglobulin production by mouse spleen lymphocytes
(https://www.tandfonline.com/doi/full/10.1080/09168451.2014.930323)
7) "Therapies from Fucoidan; Multifunctional Marine Polymers"
https://www.mdpi.com/1660-3397/9/10/1731/htm
8) Fucoidan reduces the toxicities of chemotherapy for patients with unresectable advanced or recurrent colorectal cancer  https://www.spandidos-publications.com/10.3892/ol.2011.254
9) JHFA is a certificate given to health foods that comply with voluntary food standard set by the Japan Health and Nutrition Food Association (JHNFA). JHNFA is a public interest incorporated foundation authorized by the Cabinet Office with the aim of promoting public health (http://www.jhnfa.org/english-info.html).





The above results show that fucoidan, whether through basic in vitro to in vivo research studies or clinical trials in humans, has been proven to produce effect of adjuvant therapy on cancer treatment. This allows molecular mechanisms in cancer research to be applied in adjuvant treatment, in line with the pursuit of translational medicine and the mindset of establishing a direct link between basic medical research and clinical application.

In conclusion, understanding the mechanisms underlying the anti-cancer effects of fucoidan, the advantages of combining fucoidan with therapeutic agents in the treatment of cancers, and the pharmacological limitations of fucoidan will aid the development of more informed approaches to treating cancers and may improve current clinical outcomes for cancer patients.



References:
0. 4. Kylin H. Biochemistry of sea algae. HZ Physiol. Chem. 1913;83:171–197. doi: 10.1515/bchm2.1913.83.3.171. [CrossRef] [Google Scholar]

1. Kwak J.Y. Fucoidan as a marine anticancer agent in preclinical development. Mar. Drugs. 2014;12:851–870. doi: 10.3390/md12020851. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

2. Hu Y., Cheng S.C., Chan K.T., Ke Y., Xue B., Sin F.W., Zeng C., Xie Y. Fucoidin enhances dendritic cell-mediated t-cell cytotoxicity against ny-eso-1 expressing human cancer cells. Biochem. Biophys. Res. Commun. 2010;392:329–334. doi: 10.1016/j.bbrc.2010.01.018. [PubMed] [CrossRef] [Google Scholar]

Main sources:
4. Fucoidan and Cancer: A Multifunctional Molecule with Anti-Tumor Potential
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413214/

5. Fucoidan Extracted from Undaria pinnatifida: Source for Nutraceuticals/Functional Foods
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164441/#B4-marinedrugs-16-00321

6. NIH clinical trial testing remdesivir plus interferon beta-1a for COVID-19 treatment begins
 https://www.nih.gov/news-events/news-releases/nih-clinical-trial-testing-remdesivir-plus-interferon-beta-1a-covid-19-treatment-begins

7. Albrengues J, Shields MA, Ng D, Park CG, Ambrico A, Poindexter ME, Upadhyay P, Uyeminami DL, Pommier A, Küttner V, Bružas E, Maiorino L, Bautista C, Carmona EM, Gimotty PA, Fearon DT, Chang K, Lyons SK, Pinkerton KE, Trotman LC, Goldberg MS, Yeh JT, Egeblad M (2018) Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361:1314–1315

7.5 Grivennikov SI, Greten FR, Karin M (2010) Immunity, Inflammation, and Cancer. Cell 140(6):883–899

8. FDA: Frequently Asked Questions on the Emergency Use Authorization for Remdesivir for Certain Hospitalized COVID-19 Patients -  https://www.fda.gov/media/137574/download

9. SpringerOpen: https://clintransmed.springeropen.com/articles/10.1186/s40169-019-0234-9 (open access)

10. Kadena K, Tomori M, Iha M, Nagamine T (2018) Absorption study of mozuku fucoidan in japanese volunteers. Mar Drugs 16:254. https://doi.org/10.3390/md16080254

11. https://www.mdpi.com/1660-3397/16/8/254