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Polysaccharide found in the
seaweed kombu, Fucoidan, discovered to cause cancer cells to
self-destruct
Biomedical Research
Laboratories of Takara Shuzo (CEO Hisashi Omiya) and Research Institute for
Glycotechnology Advancement, a company funded by the Bio-oriented Technology
Research Institute (CEO: Kazue Fukushi), have discovered that a
polysaccharide known as Fucoidan, which is found in kombu and other
types of brown seaweed (wakame, mozuku, and hijiki), causes various
types of established cancer cell lines to self-destruct.
1. What is Fucoidan?
About 4% percent of the total dry weight of many types of brown seaweed,
such as kombu, consists of a polysaccharide known as fucoidan. Fucoidan is a
sulfated polysaccharide that possesses a complex structure. Its chief
components include a sulfuric esterified L-fucose, and trace elements of
galactose, xylose, and glucuronic acid.
Working in conjunction,
Takara Shuzo's Biomedical Research Laboratories and Research Institute for
Glycotechnology Advancement were able to confirm the presence of two
different types of fucoidan molecules in brown seaweed. The first type,
bearing the name F-fucoidan, consists mainly of sulfated fucose. The second
type bears the name Fucoidan and approximately 20% of it consists of
glucuronic acid.
Researchers at both
institutions were able to use a technique known as pyridlamination,
developed by Takara Shuzo in conjunction with the University of Osaka, to
shed light on the chemical structure of Fucoidan.
2.
The biological activity of Fucoidan
Numerous accounts have ascribed to fucoidan properties such as the ability
to act as an anti-contraceptive, to reduce cholesterol levels, and to act as
an anti-tumor agent. However, a definitive consensus concerning the precise
nature of fucoidan has still not been reached. The Biomedical Research
Laboratories of Takara Shuzo and the Research Institute for Glycotechnology
Advancement have focused their attention on the anti-tumor properties of
fucoidan, and have managed to confirm that this substance causes certain
types of rapidly growing cancer cells to self-destruct. Examples of cancer
cell strains where this self-destruct phenomenon was observed include human
acute promyelocytic leukemia cells (HL-60 cell line), human stomach cancer
cells (AGS cell line), human colon cancer cells (HCT-116 cell line), and
cancer cells of the descending colon (SW-480 cell line/WiDr cell line).
Moreover, this self-destruction was observed to take place without affecting
normal cells. Currently, efforts are underway to clarify the precise
mechanism by which this phenomenon occurs.
Some of the reasons which
have until recently prevented the formation of a definitive scientific
consensus concerning the precise nature of fucoidan include the fact that it
possesses an extremely complex structure, as well as the difficulty of
obtaining pure samples of fucoidan. Both Takara and Research Institute for
Glycotechnology Advancement strove to overcome these difficulties, and after
having managed to produce pure samples of fucoidan, carried out the studies
that led to the above conclusions.
3. The mechanism
through which cancer cells self-destruct
In the presence of certain substances, as well as under other unusual
environmental conditions, cells may self-destruct and disappear altogether.
This self-destruct phenomenon is known as apoptosis, and is to be properly
distinguished from necrosis, which is the death of cells directly brought
about by external stimuli such as poisonous substances and physical damage
to the cell.
Properly speaking, apoptosis
is brought about by a mechanism that is programmed into the natural makeup
of cells. Organisms activate this mechanism when necessary, and once the
apoptosis mechanism has been triggered, the genetic blueprint of the cell
(DNA) is rendered useless through activation of the deoxyribonuclease found
within the cell itself. Apoptosis thus may said to be a natural means
through which living organisms manage to eliminate harmful cells from their
systems.
4. The significance of
this discovery and future prospects
From ancient times (dating from the Jomon era, approximately before the 2nd
century B.C onwards), brown seaweed has been a mainstay of the traditional
Japanese diet. It is precisely these seaweeds that contain the Fucoidan
that serve to trigger the apoptosis mechanism described above.
The prefecture of Okinawa,
whose inhabitants enjoy some of the highest life expectancies in Japan, also
happens to have one of the highest per capita consumption rates of kombu-1
gram per person per day. It is noteworthy that the cancer death rate in
Okinawa is the lowest of all the prefectures in Japan.
The average per capita
consumption rate of kombu in Japan is approximately 0.5 grams per day. Such
a serving of kombu would include roughly 5 mg of Fucoidan. In vivo
experiments are currently underway to determine the effects of Fucoidan
within living organisms. If it is confirmed that Fucoidan can help bring
about apoptosis solely in cancer cells that are multiplying at uncontrolled
rates, we would then have within our reach the long-dreamt of cancer
drug-one that does its job without causing adverse side effects.
Details of the above
discovery were disclosed at the 18th Annual Conference of the Carbohydrate
Symposium (August 19-21), the 69th Annual Proceedings of the Japanese
Biochemical Society (August 26-30), and the 55th Annual Proceedings of the
Japanese Cancer Society (October 10-12) in the year of 2000.
Details concerning the Research Institute for Glycotechnology Advancement:
With funding from the Bio-oriented Technology Research Advancement Institute
(a special legal person under the joint jurisdiction of the Ministry of
Agriculture, Fisheries and Forestry and the Ministry of Finance), Aomori
prefecture, Hirosaki city, as well as eleven private sector companies, the
Research Institute for Glycotechnology Advancement was founded in February
1991. The Institute ranks as a research organization operating under the
auspices of the Intelligent Research Institute, a body that was formed as
part of the overall efforts to promote the development of the Tohoku
(northeast) area.
Name of research project: Glycobiology research aimed at the development of
useful carbohydrates
Research time span: 7 years (1990 to 1996)
Details concerning the Institute
Name of company: Research Institute for Glycotechnology Advancement Address:
82-4 Oazazaifu-cho Hirosaki-shi Aomori-ken Japan
FUCOIDAN RESEARCH MATTERS
Blockade of
Selectin-Mediated Leukocyte Adhesion Improves Postischemic Function in Lamb
Hearts
Takuya Miura, MD, David P. Nelson, MD, Marc
L. Schermerhorn, MD, Toshiharu Shin'oka, MD, Gregor Zund, MD, Paul R.
Hickey, MD, Ellis J. Neufeld, MD, John E. Mayer, Jr, MD
Departments of Cardiovascular Surgery, Pediatrics,
Cardiology, and Anesthesia, Children's Hospital and
Harvard
Medical
School,
Boston,
Massachusetts
Background.
Leukocyte-endothelial interactions appear to have an important
role in ischemia/reperfusion injury and are mediated by specific
leukocyte and endothelial adhesion molecules. The selectins are
adhesion molecules found on leukocytes (L-selectin) and
endothelium (P and E selectin) that bind to oligosaccharide
ligands containing fucose and sialic acid to mediate leukocyte
rolling on the endothelium. Fucoidin is a nontoxic sulfated
fucose oligosaccharide derived from
seaweed
that blocks the selectins.
Methods.
`We tested the effects of fucoidin in an isolated blood-perfused
neonatal (age range, 3 to 7 days; mean age, 4.3 days) lamb heart
model undergoing 2 hours of cold cardioplegic ischemia. In group
F (n = 8) fucoidin (30 mg/L) was added at initial reperfusion.
Group C (n = 9) received only cardioplegia with no reperfusion
intervention. Isovolumic maximum developed pressure and the
maximum positive and negative first derivatives of pressure were
measured using a catheter-tip transducer in an intraventricular
balloon before ischemia and at 30 minutes of reperfusion. Coronary
blood flow, myocardial oxygen consumption, and white blood cell
counts in the circulating blood were also measured.
Results.
Percent recoveries of baseline maximum developed pressure and
maximum positive and negative first derivatives of pressure in
group F (86% ± 5%, 81% ± 10%, and 74% ± 8%, respectively; mean ±
standard deviation) were higher than in group C (77% ± 5%, 70% ±
9%, and 65% ± 6%; p < 0.05). Group F postischemic coronary
blood flow was greater (190% ± 35%) than in group C (102% ± 10%;
p < 0.05). Recovery of myocardial oxygen consumption in group
F (86% ± 14%) was greater than group C (72% ± 11%; p
< 0.05). Postischemic white blood cell count in group F (88% ±
4%) was greater than in group C (81% ± 5%; p < 0.05).
Conclusions.
Selectin blockade with fucoidin resulted in better recovery of
left ventricular function, coronary blood flow, and myocardial
oxygen consumption after cold ischemia, despite a higher
circulating white blood cell count. These data support the
hypothesis that endothelial-leukocyte interactions play an
important role in ischemia/reperfusion and suggest that selectin
blockade may be a useful therapeutic strategy.
Cell Res
1998 Mar 15;239(2):301-10
Sulfated glycosaminoglycans enhance tumor cell invasion in
vitro by stimulating plasminogen activation.
Brunner G, Reimbold K, Meissauer A, Schirrmacher V, Erkell LJ
Division of Cellular
Immunology, German Cancer Research Centre, Heidelberg, Germany.
Georg.Brunner@man.ac.uk
Metastasizing tumor cells
invade host tissues by degrading extracellular matrix constituents. We
report here that the highly sulfated glycosaminoglycans, heparin and heparan
sulfate, as well as the sulfated polysaccharide, fucoidan, significantly
enhanced tumor cell invasion in vitro into fibrin, the basement membrane
extract, Matrigel, or through a basement membrane-like extracellular matrix.
The enhancement of tumor cell
invasion was due to a stimulation of the proteolytic cascade of plasminogen
activation since the effect required plasminogen activation and was
abolished by inhibitors of urokinase-type plasminogen activator (uPA) or
plasmin. Sulfated polysaccharides enhanced five reactions of tumor-cell
initiated plasminogen activation in a dose-dependent manner. They amplified
plasminogen activation in culture supernatants up to 70-fold by stimulating
(i) pro-uPA activation by plasmin and (ii) plasminogen activation by uPA.
(iii) In addition, sulfated polysaccharides partially protected plasmin from
inactivation by alpha 2-antiplasmin. Sulfated polysaccharides also
stimulated tumor-cell associated plasminogen activation, e.g., (iv) cell
surface pro-uPA activation by plasmin and (v) plasminogen activation by cell
surface uPA. These results suggest that sulfated glycosaminoglycans
liberated by tumor-cell mediated extracellular matrix degradation in vivo
might amplify pericellular plasminogen activation and locally enhance tumor
cell invasion in a positive feedback manner.
PMID: 9521847, UI: 98189141
Anticancer Res
1996 May-Jun;16(3A):1213-8
Antitumor and antiproliferative effects of a fucan extracted
from ascophyllum nodosum against a non-small-cell bronchopulmonary carcinoma
line.
Riou D, Colliec-Jouault S, Pinczon du Sel D, Bosch S,
Siavoshian S, Le Bert V, Tomasoni C, Sinquin C, Durand P, Roussakis C
ISOMer (Institut des
Substances et Organismes de la Mer), SMAB, Laboratoire de Pharmacologie
Marine, Faculte de Pharmacie, Nantes, France.
Fucans, sulfated
polysaccharides extracted from brown seaweeds, have been shown to be endowed
with inhibitory effects cell growth in various experimental models. We
studied both the antiproliferative and antitumor properties of a fucoidan
extract (HF) obtained from the brown seaweed Ascophyllum nodosum on a cell
line derived from a non-small-cell human bronchopulmonary carcinoma
(NSCLC-N6), this type of carcinoma is particularly chemo-resistant. HF
exerts in vitro a reversible antiproliferative activity with a block
observed in the G1 phase the cell cycle. Studies performed with the
NSCLC-bearing nude mice show antitumor activity at subtoxic doses. These
preliminary results indicate that HF exhibits inhibitory effect both in
vitro and in vivo and is very potent antitumor agent in cancer therapy.
PMID: 8702239, UI: 96273150
Eur J Haematol
1995 Jan;54(1):27-33
Changes in adhesion molecule expression and function in
B-cell chronic lymphocytic leukaemia after in vitro interferon-alpha
stimulation.
Csanaky G, Vass JA, Ocsovszki I, Milosevits J, Szomor A,
Schmelczer M
Department of Pathology,
University Medical School of Pecs, Hungary.
Peripheral blood mononuclear
cells (PBMCs) from 10 B-CLL patients were investigated after 24 hours of in
vitro interferon-alpha (IFN-alpha) stimulation. The constitutional
expression of the L-selectins (LECAM-1), LFA-1/CD11a, VLA alpha-4/CDw49d and
ICAM-1/CD54 adhesion molecules was detected, and changes in their density
after IFN-alpha stimulation were compared to results obtained by the high
endothelial venule (HEV)-binding assay and a carbohydrate (phosphonomannan
core polysaccharide: PPME and fucoidin) immobilization test. The LECAM-1 and
ICAM-1 molecules were expressed on the great majority of CLL cells, while
the LFA-1 and VLA-4 alpha-chains were expressed by only a small number of
cells. Statistically significant changes (p < 0.001) were observed in
LECAM-1 antigen density (changes in mean cell fluorescence), as well as in
functional tests (HEV-, PPME- and fucoidin-binding; p < 0.01) after in vitro
IFN-alpha stimulation. Based on a prior study (Jewell et al., Leukemia 1992:
6: 400-404) and on the present findings, not only an increased expression
but also an enhanced function of the L-selectins seem to be well
substantiated after IFN-alpha stimulation, which may explain the therapeutic
effect of IFN-alpha in reducing the accumulation of leukaemic B cells in the
blood. The remarkably high expression of ICAM-1 in this series necessitates
further studies to clarify the exact expression rate and role of this
molecule.
PMID: 7532138, UI: 95163724
Jpn J Cancer Res
1994 Nov;85(11):1144-50
Inhibitory effect of oversulfated fucoidan on invasion
through reconstituted basement membrane by murine Lewis lung carcinoma.
Soeda S, Ishida S, Shimeno H, Nagamatsu A
Department of Biochemistry,
Faculty of Pharmaceutical Sciences, Fukuoka University.
We investigated the effects
of native, oversulfated, and desulfated fucoidans and heparin on the
invasion of 3 LL cells through Matrigel. Of the four polysaccharides tested,
oversulfated fucoidan was the most potent inhibitor of tumor cell invasion
and inhibited most potently and specifically the tumor cell adhesion to
laminin. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis
of the binding of elastase-cleaved laminin to fucoidan- and
heparin-Sepharoses showed that both polysaccharides bound to the 62 and 56
kDa fragments. Pretreatment of 3LL cells with native or oversulfated
fucoidan reduced their adhesive potency to laminin. The two fucoidans
inhibited further the laminin binding of 3 LL cells which had been
pretreated with a laminin-based pentapeptide, YIGSR. These results suggest
that fucoidan specifically binds to not only the heparin binding domain(s)
of laminin but also site(s) other than the cell surface laminin receptor. 3
LL cells secreted a 50 kDa form of urokinase-type plasminogen activator
(u-PA). The extracellular level of u-PA activity was increased 1.7 times by
addition of laminin but not type IV collagen. Oversulfated fucoidan most
potently reduced the increased u-PA levels. Therefore, the reduction in in
vitro invasiveness of 3 LL cells in response to either fucoidan or its
oversulfated derivative may result from an inhibition of physical
interaction between the tumor cells and the Matrigel (laminin), followed by
a suppression of the laminin-induced increase in extracellular u-PA.
PMID: 7829400, UI: 95130424
Cancer Lett
1994 Sep 30;85(1):133-8
Aminated fucoidan promotes the invasion of 3 LL cells through
reconstituted basement membrane: its possible mechanism of action.
Soeda S, Ishida S, Honda O, Shimeno H, Nagamatsu A
Department of Biochemistry,
Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.
Fucoidan is reported to have
an antimetastatic activity. In the present study, we prepared an amino
group-introduced derivative of fucoidan and examined its effect on the
invasion of 3 LL cells through a reconstituted basement membrane
(MatrigelTM). Unlike native fucoidan, the aminated derivative promoted the
tumor cell invasion: maximal promotion (240% of control invasion) was
obtained with 5 micrograms/ml. However, with higher concentrations (10-30
micrograms/ml) of the fucoidan derivative, the promotion was gradually
reduced to 130% of control. Both native and aminated fucoidans inhibited
specifically the attachment of 3 LL cells to laminin. Interestingly,
aminated fucoidan, unlike the native one, promoted the tumor cell adhesion
to immobilized synthetic laminin B 1 chain peptide, YIGSR, over a
concentration range of 0.5-5 micrograms/ml. Higher concentrations (7-20
micrograms/ml) of the aminated derivative suppressed the adhesive ability of
3 LL cells to YIGSR. 3 LL cells secreted a 50-kDa form of urokinase-type
plasminogen activator (u-PA) in the culture medium. Addition of aminated
fucoidan (5 micrograms/ml) or YIGSR (10 micrograms/ml) resulted in a
1.7-fold increase in u-PA activity. This effect was enhanced up to 3.5-fold
when both substances were simultaneously added. The addition of native
fucoidan had no effect. The present results suggest that the 67-kDa
receptor-mediated binding of 3 LL cells to laminin activates their
invasiveness, especially by enhancing the extracellular u-PA levels.
Aminated, but not native, fucoidan may act to enhance the laminin-receptor
interaction at the limited concentration range.
PMID: 7923097, UI: 95007484
Anticancer Res
1993 Nov-Dec;13(6A):2045-52
Antitumor activity and immunological properties of marine
algal polysaccharides, especially fucoidan, prepared from Sargassum
thunbergii of Phaeophyceae.
Itoh H, Noda H, Amano H, Zhuaug C, Mizuno T, Ito H
Laboratory of Marine
Biochemistry, Faculty of Bioresources, Mie University, Japan.
Marine algal polysaccharide,
GIV-A from Sargassum thunbergii markedly inhibited the growth of Ehrlich
ascites carcinoma at the dose of 20 mg/kg per day X10 with no sign of
toxicity in mice. GIV-A is suggested to be a hexouronic acid containing
L-fucan sulfate, fucoidan by the analyses of physicochemical properties and
IR- and NMR-spectra. The results of carbon clearance activity with fucoidan
demonstrated that it is acting as a so-called activator of the
reticuloendothelial system. Fucoidan enhanced the phagocytosis and
chemiluminescence of macrophages. By the immunofluorescent method, binding
of the third component of complement (C3) cleavage product to macrophages
and the proportion of C3 positive cells were increased. In crossed
immunoelectrophoresis, human serum C3 was converted by fucoidan and appeared
as the 3rd peak (converted C3). The height of the 3rd peak was directly
proportional to the doses of fucoidan. The residual CH50 units of human
serum decreased dose-dependently. These results suggest that the antitumor
activity of fucoidan is related to the enhancement of immune responses. The
present results indicate that fucoidan may open new perspectives in cancer
chemotherapy.
PMID: 8297113, UI: 94127818
Laryngorhinootologie
1991 May;70(5):243-9
[Histochemical identification of endogenous lectins using
labelled neoglycoproteins in human head-and-neck squamous cell carcinoma].
[Article in German]
Steuer MK, Gabius HJ, Bardosi A, Matthias R
Klinik und Poliklinik fur
Hals-Nasen-Ohrenheilkunde, Universitat Koln.
According to the
"Population-based cancer register" of the Federal Republic of Germany only
malignant neoplasms of the buccal cavity, the pharynx and larynx as well as
cancers of the respiratory tract show an increasing rate of incidence and
mortality. The molecular mechanisms and etiological factors causing this
phenomenon are still little understood despite intensive research work.
Recognition between receptors on a cellular level may be mediated by
specific amino acid sequences on the level of protein-protein recognition.
Additionally, the interactions between cell sugars and the corresponding
protein receptor may play a decisive role in development, regeneration and
organisation of cells and tissue. The high specificity of the binding of
biotinylated neoglycoproteins in tissue sections enables to detect
glycohistochemically binding sites for the carbohydrate ligands of the
glycosylated carrier protein. The evidence of lectins in squamous cell
cancer of the oral cavity, oropharynx, larynx, and hypopharynx has not been
established so far. Squamous cell cancer tissue samples of twelve patients
with different tumour locations were investigated by incubation of sections
of paraffin-embedded samples and application of an avidin-biotin-peroxidase
complex for visualisation with synthetic biotinylated neoglycoproteins.
Altogether 168 stained sections were evaluated including controls.
Pronounced cytoplasmatic staining was seen with the following
neoglycoproteins: sialic acid-bovine serum albumin (BSA), glucuronic
acid-BSA, N-acetylglucosamine (glcNAc)-BSA, N-acetylgalactosamine
(beta-galNAc)-BSA, lactose-BSA, maltose-BSA, mannose-BSA,
mannose-6-phosphate-BSA. No corresponding lectins seems to exist for the
following investigated sugars: fucoidan, heparin, and the alpha-anomeric
form of N-acetylgalactosamine, because no specific staining was seen.
Publication Types:
PMID: 2064700, UI: 91291219
Experientia
1989 Jun 15;45(6):584-8
Blocking of lectin-like adhesion molecules on pulmonary cells
inhibits lung sarcoma L-1 colonization in BALB/c-mice.
Roszkowski W, Beuth J, Ko HL, Uhlenbruck G, Pulverer G
National Institute of Lung
Diseases and Tuberculosis, Warsaw, Poland.
Adhesion and inhibition
experiments with pulmonary cells of BALB/c-mouse origin and syngeneic
sarcoma L-1 cells indicated that L-fucose specific lectin-like adhesion
molecules, presumably situated on pulmonary cell surfaces are (at least
partly) responsible for the specificity of this cell-cell interaction.
Addition of specific sugars and glycoconjugates (L-fucose and fucoidan,
respectively) to the incubation medium evidently inhibited the adhesion
process as quantified using radiolabelled tumor cells. Unspecific
carbohydrates (e.g. D-galactose) did not affect the cellular interaction. In
vivo, repeated administration of fucoidan (but not of unspecific
glycoconjugates) significantly inhibited the settling of metastatic sarcoma
L-1 cells in the lungs of BALB/c-mice. Therefore, when lectin-like adhesion
molecules on pulmonary cells were blocked with competitive glycoconjugates,
tumor cell colonization of the lung could be significantly inhibited.
PMID: 2737266, UI: 89289934
Hum Pathol
1989 Apr;20(4):352-60
Histopathologic evaluation of application of labeled
neoglycoproteins in primary bronchus carcinoma.
Kayser K, Gabius HJ, Ciesiolka T, Ebert W, Bach S
Department of Pathology,
Thoraxklinik Heidelberg-Rohrbach, Germany.
Neoglycoproteins are readily
available conjugates of a histochemically inert carrier protein and
histochemically crucial carbohydrate moieties which are covalently attached
to the carrier protein by chemical synthesis. Biotinylation renders these
conjugates detectable in formalin-fixed, paraffin-embedded tissue sections
of human lung cancer by standard staining protocols, thereby localizing
endogenous receptors for carbohydrate moieties. Examination of 30 cases of
main types of human lung cancer revealed the presence of alpha-fucosyl-,
alpha-mannosyl-, and alpha-glucosyl-specific receptors in adenocarcinomas or
epidermoid carcinomas with high positivity rates. The extent of the
expression of receptors for alpha- and beta-galactosides appeared to be
comparatively lower. Within the standard protocol, using a concentration of
the biotinylated probes of 10 micrograms/mL, this panel of probes
consistently failed to detect endogenous sugar receptors in ten cases of
small cell anaplastic carcinoma of the lung. Whereas none of the sections
from the tumor cases bound the sulfated fucan fucoidan, the accompanying
inflammatory cells, especially the granulocytes, expressed receptors for the
sulfated fucan. Pronounced labeling for macrophages was observed for the
alpha-galactoside-specific probe, whereas no binding to inflammatory cells
and pneumocytes was detectable for the beta-galactoside-specific probe. The
results indicate that expression of endogenous receptors for
neoglycoproteins may be useful in discriminating between small cell and
non-small cell lung carcinoma and carcinomatous cells from accompanying
inflammatory cells.
PMID: 2467870, UI: 89197199
Cancer Res
1988 Jun 15;48(12):3367-73
Laminin-dependent and laminin-independent adhesion of human
melanoma cells to sulfatides.
Roberts DD, Wewer UM, Liotta LA, Ginsburg V
Laboratory of Structural
Biology, National Institute of Diabetes and Digestive and Kidney Diseases,
Bethesda, Maryland 20892. </ | 
