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Brown Seaweed Fucoidan in Cancer: Implications in Metastasis and Drug Resistance

Laboratory of Integrative Biology (LIBi), Center of Excellence in Translational Medicine- Scientific and Technological Bioresource Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco 4710296, Chile
Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco 4810101, Chile
Precision Health Research Laboratory, Departamento de Procesos Diagnósticos y Evaluación, Facultad Ciencias de la Salud, Universidad Católica de Temuco, Temuco 4813302, Chile
Author to whom correspondence should be addressed.
María Elena Reyes & Ismael Riquelme contributed equally to this work.
Mar. Drugs 2020, 18(5), 232;
Submission received: 16 March 2020 / Revised: 18 April 2020 / Accepted: 19 April 2020 / Published: 28 April 2020
(This article belongs to the Special Issue Fucoidans)


Fucoidans are sulphated polysaccharides that can be obtained from brown seaweed and marine invertebrates. They have anti-cancer properties, through their targeting of several signaling pathways and molecular mechanisms within malignant cells. This review describes the chemical structure diversity of fucoidans and their similarity with other molecules such as glycosaminoglycan, which enable them to participation in diverse biological processes. Furthermore, this review summarizes their influence on the development of metastasis and drug resistance, which are the main obstacles to cure cancer. Finally, this article discusses how fucoidans have been used in clinical trials to evaluate their potential synergy with other anti-cancer therapies.

1. Introduction

Fucans are a family of polymeric molecules composed by a simple and long structure based on fucose and sulphate. Fucoidans are a subgroup within the fucan family, consisting of polysaccharides that are composed of sulphated l-fucose (6-deoxy-l-galactose) produced mainly by brown algae and, to a lesser extent, by marine invertebrates [1].
Due to the structural similarity between fucoidans and certain sulphated polysaccharides from animal cells, there has been increasing interest to study the biological properties of these algae polysaccharides within animal cells. An example for this are proteoglycans, which are found on the surface of animal cells and the extracellular matrix (ECM) and participate in structural and support functions. They have been shown to regulate a series of intercellular signaling pathways and interactions with cytokines and growth factors [2]. The structure of proteoglycans is similar to fucoidans, being composed of a protein (central chain) with glycosaminoglycans (GAGs) ramifications (e.g., chondroitin, dermatan, keratan, heparan sulphates, and heparin). This finding has sparked a renewed interest for studying the numerous potential biological properties including the anticoagulant [3], antioxidant [4], antiviral, immunomodulatory, anticomplement, and antitumor [5] characteristics of fucoidans isolated from different brown algae species.
The chemical variety of fucans in algae and invertebrate, their abundant bioavailability in nature as a renewable natural resource available from our coasts [5] and their potential use for biomedicine, make these polysaccharides an interesting material to study. This review will reveal not only structural characteristics but also the cellular/molecular aspects of fucoidans and their potential applications for cancer due to their properties to reduce metastasis and drug resistance in the different in vivo and in vitro cancer models.

2. General Structure of Fucoidans

Fucoidans from algae have been extensively studied since 1913 when Prof. Kylin discovered and described fucoidans [6]. Then, in 1957 these molecules were also shown to have anticoagulant functions and subsequently their anticancer activities were demonstrated (1970) [7].
As described above, fucoidans are polysaccharide composed by sulphated l-fucose (6-deoxy-l-galactose) [8]. Although many fucoidans consist of fucose and sulphate groups as is typical for fucans in general, fucoidans—in contrast to other fucans—consist of up to 10% of other monosaccharides (mannose, galactose, glucose, xylose, etc.), uronic acids, or branches of one or more monosaccharides [5]. In addition, there are fucoidans with different monosaccharide residues alternating with α (1→3) and α (1→4) bonds. Therefore, fucoidans constitute a highly variable and versatile subgroup of fucans [9] (Figure 1).
For instance, fucoidans from Fucus vesiculosus are composed of l-fucopyranosil residues linked through α (1→2) bonds with 4-position sulphate groups [10]. In addition, next generation techniques have shown that the scaffold is also composed by fucose residues linked through α (1→3) bonds with 4-position sulphate groups from some of the fucose residues disposed every two or three units of the main chain [11]. In contrast, other algae species contain the typical fucan complexes. Sargassum stenophyllum contains two types of fucans: (1) fucans containing predominantly α-l-fucose with high percentage of glucuronic acid and low amounts of sulphate located in different positions in the sugar [12] (2) fucans containing high amounts of sulphate but lower content of uronic acids distributed along the fucose chains or the only other sugar, galactose [12].
A wide range of l-fucose polymers has been found by fractionating the extracts from different algae species within the brown seaweed genus [3,13,14,15,16,17,18,19,20]. These fucoidans range from fractions of typical sulphated fucoidans to heteropolymer fractions of low-sulphate fucose and others containing glucosamine. The fucoidan structures vary from species to species, by season, location and maturity [21]. This structural variations are important for industrial applications to identify the optimum harvesting times and to ensure a consistent product composition. For instance, Fletcher et al., 2017 found that the highest quantity of fucoidans can be extracted from three algae F. serratus, F. vesiculosus, and Ascophyllum nodosum in autumn, whereas in spring the amount that can be obtained is at a minimum [21].
In addition to brown seaweed species, also marine invertebrates contain this type of sulphated polysaccharides. The viscous liquid containing sea urchin eggs, such as that of the Strongylocentrotus franciscanus species, contains a compound composed by sulphate acids residues only in position 2 bonds through α (1→3) bonds [22]. Other fucoidans have been found in the skin of the sea cucumber species Stichopus japonicas [23] and the recently commercially important Holothuria tubulosa [24].
The great diversity of fucoidans and their capability to be chemically modified make them molecules with great potential to be used as adjuvant agents in the treatment of cancer.

3. Fucoidans and Metastasis

In cancer, many cells develop the ability to invade adjacent tissue components of its primary organ and spread to other organs [25]. This process is called metastasis and involves several steps including altered cellular adhesions, cell motility, resistance to extracellular death signals, and disruption of the basement membrane and ECM [26]. Metastasis is responsible for more than 90% of cancer deaths [27] due to its systemic nature and higher drug resistance. Therefore, new molecular or clinical strategies are needed to counteract this aggressive feature [28]. In general, the metastasis process can be divided into 4 steps: (1) Certain tumor cells obtain characteristics of epithelial–mesenchymal transition (EMT), dissociating and detaching from the primary tumor to escapes from this area. (2) The dissociated tumor cells infiltrate into the surrounding stroma and invade and migrate through the basement membrane supporting the endothelium of local blood and/or lymphatic vessels. (3) The dissociated tumor cells cross the ECM resulting in intravasation. This involves dissemination of tumor cells to distant organs through blood or lymph vessels. These tumor cells can then forma new tumor in other organs or tissues (secondary tumor) through mesenchymal to epithelial transition (MET), which is another mechanism that enables metastatic colonization (neoplasm) and that is the contrary to EMT (e.g., re-expression of E-cadherin). (4) The final dormancy step is characterized by invading tumor cells that can remain silent for many years in the distant organ [29]. Both step 1 (EMT) and 2 (infiltration and invasion into stroma) are characterized by morphological changes from the epithelial cell monolayer with an apical-basal polarity, to dispersed, spindle-shaped mesenchymal cells with migratory protrusions [30]. In particular, EMT involves changes in the expression of cell–cell junction proteins, cytokeratin intermediate filaments, increase vimentin filaments and fibronectin [31]. In this case, sulphated fucoidans have been shown to maintain the endothelium adhesion by binding to endothelial cell receptors, especially when the polysaccharides that normally bind to these receptors decrease, confirming that fucoidans have antimetastatic effects and can prevent EMT [32]. A recent study demonstrated this using fucoidan from F. vesiculosus, which was able to inhibit the EMT and, therefore, an important step in the metastasis development [33]. In addition, fucoidan has been shown to decrease the activity or expression of transforming growth factor receptors (TGFRs) in vitro and in vivo. This blocks the EMT process and its morphological changes by upregulating epithelial markers, downregulating mesenchymal markers and decreasing the expression of transcriptional repressors such as SNAIL, SLUG, and TWIST, which subsequently induce migration and invasion inhibition [34]. Moreover, fucoidans are also able to reduce TGFR downstream signaling events, including SMAD2/3 and non-SMAD pathways: AKT, ERK1/2, and Focal Adhesion Kinase (FAK) phosphorylation. Fucoidans decrease TGFR proteins by ubiquitination proteasome pathway (UPP)-mediated degradation of TGFRs and by the promotion of SMURF2 and SMAD7 that conjugate to TGFRs, resulting in TGFR degradation [35].
Post-transcriptional mechanisms have also been implicated in the control of EMT and their relationship to TGF-β signaling through microRNAs (miRs). In this context, fucoidan of S. hemiphyllum, increases the miR-29 family expression that suppresses DNMT3B expression, which results in the upregulation of the tumor suppressor gene MTSS1. This fucoidan also downregulates TGF-β signaling, increases E-cadherin expression, decreases N-cadherin, ADAM12, and PTEN expression, and finally prevents ECM degradation by overexpressing TIMP-1 and reducing the expression of matrix metalloproteinase enzymes MMP2 and MMP9, secreted by cancer cells to degrade ECM and induce cell migration [36,37]. Furthermore, an oligo-fucoidan extracted from S. hemiphyllum has been shown to inhibit the signaling of chemokine CCL2, which has a chemoattractant activity for monocytes, T cells, mast cells and basophils, and promotes invasion and metastasis via JAK-STAT and MAPK signaling pathways. Therefore, this CCL2 inhibition induces an inflammatory response, anti-tumor immunity and tissue conservation to avoid metastasis and angiogenesis [18]. Another example is the fucoidan of S. fusiforme which has an antimetastatic effect on liver cancer cells by inactivating the integrin αVβ3 and prevent the invadopodia formation [38].
Another characteristic of metastasis is the involvement of cell migration and invasion properties through ECM [30]. As fucoidans have structural similarities with heparin, these polysaccharides not only have anticoagulant features but also are able to decrease the expression and activity of matrix metalloproteinases, resulting in an incapability of tumor cells to cross the capillary wall [39]. For example, fucoidan derived from Undaria pinnatifida sporophylls inhibits in vitro cell growth, migration, invasion, and adhesion capabilities probably by downregulating the VEGFC/VEGFR3 axis, inactivating the NF-kB pathway and increasing the protein levels of TIMPs [40]. Other fucoidans decrease the expression levels of MMP2 in a dose dependent manner and downregulate the PI3K/Akt/mTOR signaling pathway [41].
Fucoidan of Laminaria japonica reduce the migratory and invasive features of triple-negative breast cancer (TNBC) cell models by suppressing the activation of MAPK and PI3K pathways and subsequently inhibiting AP-1 and NF-κB signaling. Additionally, this fucoidan was shown to inhibit micrometastasis in an in vivo transgenic zebrafish model [42].
Hypoxia in tumoral microenvironment is another phenomenon that can lead to metastasis. Fucoidan derived from U. pinnatifida sporophylls inhibit hypoxia in cancer cells through nuclear translocation, activity of HIF-1α and reduction in the levels of phosphorylated-PI3K (p-PI3K), p-Akt, p-mTOR, p-ERK, NF-κB, MMP-2, and MMP-9, but increased TIMP-1 levels. In addition, this fucoidan can decrease the levels of VEGF-C and HGF [43]. The most complete studies about inhibition of metastasis and drug resistance by fucoidans are shown in Table 1 and the main signaling pathways involved in these processes are shown in Figure 2.
Given the biological activities and implications of fucoidans in cancer, particularly in metastasis, the sulphated polysaccharides are candidates to generate functional foods and drugs as well as for their applications in prevention, synergism with chemotherapy, and nanotechnology. For instance, one nanotechnology application is the utilization of polysaccharides by eco-friendly synthesis of fucoidan-stabilized gold nanoparticles for charge interaction [44]. This demonstrates the potential of fucoidan to be used as a therapeutic agent and as technological material.

4. Fucoidans and Drug Resistance in Cancer

There are many types of cancer treatments, including surgery, radiation, chemotherapy, hormone therapy and, more recently, target therapy (e.g., chemokine receptors), stem cells transplantation, and immunotherapy [67]. One of the major complications in cancer treatment is the appearance of chemotherapy resistance, which is defined as the development of innate and/or acquired ability by cancer cells to evade the effects of chemotherapeutics [68]. Some cancer cells are intrinsically resistant to chemotherapy and others are able to develop a resistance phenotype, either by their own characteristics as tumor cells or by external conditions such as the tumor microenvironment [69]. For instance, repeated chemotherapeutic stimulation can induce pro-survival biological changes in tumor cells, allowing them to evade cell death under drug pressure by using host or tumor-related factors [70]. Most chemotherapeutic agents in cancer therapy (e.g., platinum drugs, taxanes) induce cell stress on “sensitive cells” resulting in cell death mediated predominantly by the apoptosis pathway [71]. Despite the effectiveness of programmed cell death induced by drugs, because tumors are heterogeneous in nature, certain cancer cells can display a drug-resistant behavior. This constitutes the main obstacle for anticancer therapeutic success [72]. There are four major mechanisms that contribute to drug resistance in cancer cells: (1) Decreased uptake of water soluble drugs [73]; (2) changes in intracellular pathways that affect the potential of cytotoxic drugs to kill cells, including alterations in the cell cycle, DNA repair, apoptosis pathways, metabolism/elimination of drugs, or others [73,74,75]; (3) increased energy-dependent efflux of hydrophobic drugs mediated via overexpression of a family of energy-dependent transporters (known as ATP-binding cassette transporters) such as P-glycoprotein 1 (P-gp, ABCB1) or breast cancer resistance protein (ABCG2) amongst others [73]; and (4) intracellular detoxifiers such as antioxidants (e.g., glutathione) [76,77]. Multiple signaling pathways have been implicated in resistance to chemotherapy, and innovative therapeutic strategies to overcome these are urgently needed [78].
Some fucoidans have been implicated in the decrease of the cancer drug resistant phenotype (Table 1). For example, fucoidans from A. nodosum showed an arrest in G1 phase of the cell cycle and a reduction in the chemoresistance to cisplatin of non-small-cell human bronchopulmonary carcinoma (NSCLC-N6) cells, a type of chemoresistant cell line [62]. The same study also showed an antitumor effect at sub-toxic doses of fucoidan in vivo in NSCLC-bearing nude mice [62]. Similarly, a sulphated fucan-like polysaccharide with aminosugar obtained from Turbinaria ornate was shown to arrest cell cycle in G1 phase in NSCLC-N6 cells [63]. A fucoidan obtained from F. veciculosus was able to decrease the expression of cellular prion protein (PrPC) HT29 colon cancer cell lines. PrPC is a protein whose overexpression is involved in increasing cell survival and proliferation, and inhibition of stress-response proteins p38, JNK, and p53, which could induce drug resistance [54,79].
More recently, cytokines have been shown not only to directly influence cancer progression by inducing cancer cell proliferation, migration, metastasis, reprogramming of tumor microenvironment (TME), immune evasion and the formation of new blood vessel within tumors [80,81] but are also often associated with chemoresistance and overall poor prognosis [80,82,83,84,85,86]. In this context, certain oligo-fucoidan have been shown to produce pro-inflammatory cytokines and chemokines (e.g., IL-6 and CCL2/MCP-1 respectively) and decrease the side effects of chemotherapy [18]. Also, other fucoidans can downregulate some cytokines and chemokines (e.g., M2-type chemokine CCL22) to inhibit tumor cell migration and lymphocytes recruitment via NF-κB-dependent transcription, which may be a novel and promising mechanism for tumor immunotherapy [46].
Fucoidans can also function as adjuvant agents along with chemotherapy. For instance, it has been demonstrated that sulphated polysaccharides can increase the bioavailability of certain oral drugs, like doxorubicin [87]. Fucoidans from U. pinnatifida and F. vesiculosus have been studied in combination with tamoxifen and paclitaxel in orthotopic mouse models of breast cancer and ovarian cancer. The results showed that both fucoidans improved the effect of tamoxifen, but not paclitaxel, in breast cancer. In the ovarian cancer model, only fucoidan from F. vesiculosus was able to improve the activity of tamoxifen, but not paclitaxel [50]. Fucoidan from F. vesiculosus has been shown to increase cytotoxicity of cisplatin on lung cancer cell lines via upregulation of cleaved caspase-3 and poly (ADP ribose) polymerase (PARP) expression, which induces apoptosis in these cells [47]. In addition, this fucoidan can also act synergistically with gefitinib to induce apoptosis in lung cancer cells [48].
Fucoidan from U. pinnatifida has also been investigated in melanoma, which is an intrinsically aggressive and therapy-resistant cancer that can develop resistance to the ERBB inhibitor, lapatinib. While, lapatinib alone inhibited 60% of tumor growth, in combination with fucoidan it decreased 85% of tumor growth. In addition, the use of fucoidan can counteract the morbidity associated with prolonged lapatinib treatment. This ability to avoid side effects provides an additional advantage for the potential use of fucoidan extracts [59]. Another fucoidan extracted from Cladosiphon navae-caledoniae Kylin in combination with cisplatin, tamoxifen or paclitaxel can improve outcomes in breast cancer treatment. These co-treatments significantly inhibited cell growth in MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, they enhanced apoptosis in these cells by downregulating anti-apoptotic proteins Bcl-xL and Mcl-1 and promoting higher intracellular ROS levels [58].
Fucoidans have particular chemical characteristics (backbone with fucose sugar and sulphate group) that confer them a negative surface and favor interaction with other chemical compounds or cellular molecules. This makes them an interesting material for the development of nanoparticles. Hwang et al. designed fucoidan-cisplatin nanoparticles with high cisplatin content and loading efficiency. These were used to treat macrophage cells (RAW264.7) to assess immune protection from the cytotoxicity of cisplatin [88]. Indeed, the cells treated with fucoidan-cisplatin conjugation were more protected in comparison to cells treated with cisplatin alone. Moreover, the fucoidan-cisplatin nanoparticles showed stronger cytotoxicity against colon cancer cell lines than those treated with cisplatin alone, which suggests that fucoidan-based nanoparticles with high drug encapsulation have a potential application in immunotherapy and chemotherapy [88]. Other nanoparticles with fucoidan-coated manganese dioxide were applied in pancreatic cancer cell models associated to hypoxia as a mechanism of resistance to radiation therapy [56]. The nanoparticles not only showed a significant decrease of HIF-1 expression under a hypoxic condition, but they were also able to reverse hypoxia-induced radioresistance. The latter was shown by a decrease of clonogenic survival and an increase of DNA damage and apoptosis in response to radiation therapy. In vivo studies showed that fucoidan-coated manganese dioxide nanoparticles along with radiotherapy also decrease tumor growth in comparison to radiation alone [56]. Therefore, fucoidan-coated manganese dioxide nanoparticles have clinical potential in the treatment of hypoxic, radioresistant pancreatic cancer [56] (Figure 2). Furthermore, a combinational synergistic effect between fucoidan (natural compound), doxorubicin (chemotherapeutic drug) and photothermal nanocarrier (Pt nanoparticle) has been observed as it was possible to reverse the drug resistance of breast cancer cells submitted to photothermal therapy [66]. In this case, the fucoidan was applied as a biocompatible surfactant and surface-coating biopolymer in the fucoidan-coated photothermal nanocarrier. As a result, the biological–chemo–thermo combination treatment showed a promising therapeutic efficiency against multidrug resistant breast cancer cell MCF-7 ADR both in in vitro and in vivo breast cancer models [66]. Fucoidan from F. vesiculosus assembled within nanoparticles bearing doxorubicin improved significantly the chemotherapy response in breast cancer cell lines by enhancing their immunostimulatory activity [51].
The molecular mechanisms of drug resistance have been classified into pre-target (alterations that precede the binding to DNA), on-target (alterations that are directly related to drug-DNA interaction), post-target (mechanisms downstream of DNA damage with effect in cell death signaling pathways) and off-target (influencing on molecular processes that are not directly associated with drug-elicited signals) [78]. In this context, the potential mechanisms in which fucoidans can reverse the drug resistance are versatile. Fucoidans can inhibit chemokine/chemokine receptors interaction as a pre-target mechanism [18]. The increase of cell cytotoxicity and arrest of the cell cycle demonstrates their effect on on-target mechanisms [62].They can influence post-target mechanisms, for example through the downregulation of anti-apoptotic proteins Bcl-xL and Mcl-1.and finally, the promotion of higher intracellular ROS levels, is an example for their role in an off-target mechanisms [58].

5. Fucoidan Clinical Trials

In general, clinical trials are used to assess if a new treatment is more effective and/or has less harmful side effects than the standard treatment. Currently, only few clinical trials have been performed to assess fucoidan in cancer. These studies tested fucoidan either as a new therapeutic agent or as diet supplement (Table 2).
There are some examples of the use of fucoidan as a complementary therapy or food supplement in complementary alternative medicine in the treatment of cancer. A review, combining five case studies, showed clinical improvement in cancer patients, mainly using low molecular weight fucoidan supplements [93]. Other clinical trials in colorectal cancer [60] and breast cancer [89] in which fucoidans were used as a co-adjuvant treatment showed a better life quality cancer survivors [91] and in patients with advanced cancers [92]. The main fucoidan effects reported in cancer patients have been the improvement of negative effects of the chemotherapy and improved immune regulation. The fucoidan from Cladosiphon okamuranus for instance, decreases the cytotoxic effect from long-term colon cancer therapy (FOLFOX and FOLFIRI). The fucoidan in this case prevents the occurrence of fatigue during chemotherapy and increases patient survival. By ameliorating side effects, it enables the constant application of therapeutic drugs [90]. Fucoidan therefore has high potential for adjuvant therapy and may improve current clinical outcomes for cancer patients [55]. However, more clinical trials and further development of fucoidan applications are required.

6. Concluding Remarks

Fucoidans are a family of sulphated polysaccharides with great diversity in their structures due to their different sulphation patterns and the types of monosaccharides that in addition to fucose make up their backbone.
In some cancer types, fucoidans can inhibit metastasis processes including EMT, migration, invasion and MET processes. Fucoidans function by altering signaling axes such as TGFR/TGF-β, PI3K/AKT, VEGF, NF-κB, or ERK1/2 pathways and by inhibiting MMPs from cancer cells. Other mechanisms in which fucoidans may prevent EMT are TGF-β inhibition regulation of microRNAs. However, many questions regarding the functional mechanisms in which fucoidans affect EMT remain, leaving the door open for future research.
The molecular characteristics of fucoidans (e.g., molecular weight and sulphation grade) enable chemical or enzymatic modifications, which make them good candidates for therapeutic use, or to use them as adjuvants to increase the therapeutic efficiency of known chemotherapeutics. Moreover, the molecular versatility of fucoidans has made them excellent precursors for the development nanoparticles. Studies have demonstrated their potential to improve the efficiency of drug delivery into the tumor and/or to achieve a synergistic effect with other cancer drugs.
However, despite these auspicious/promising results, there is a lack of information about fucoidan structure, molecular weight, sulphate amount, etc. This will be important to better understand the possible influence of fucoidans on intracellular biological activity. In addition, the use of fucoidans in different cancer models and the interpretation of the results remains challenging. Most of the time, there are controversies related to the vague establishment of the studying variables or the scarce explanation of them, which makes it difficult to compare different studies.
Although there are still multiple challenges to overcome before fucoidans can be clinically used, it is predicted that in the near future, fucoidan-based approaches may provide important advances in overcoming the most complicated cancer drawbacks including metastasis and drug resistance and improving chemotherapy response and quality of life in cancer patients. Further studies are needed to discover more fucoidans and fucoidan-related targets to acquire a better understanding of how these molecules can arrest the mechanisms of metastasis and multidrug resistance in different cancer types.

Author Contributions

Conceptualization, M.E.R., I.R., P.B.; Validation, M.E.R., I.R., T.S., P.L., P.B.; Formal analysis, M.E.R., I.R.; Data curation, M.E.R., I.R., L.Z., T.S., P.L.; Writing—original draft preparation, M.E.R., I.R.; Writing—review and editing, M.E.R., I.R., L.Z., T.S., P.L.; Visualization, M.E.R., I.R.; Supervision, P.B. All authors have read and agreed to the published version of the manuscript.


This research was funded by National Commission for Scientific and Technological Research (CONICYT) Grant 21201835 (MER). National Funding for Scientific and Technologic Development of Chile (FONDECYT) Grant 11150802 (PB), National Funding for Scientific and Technologic Development of Chile (FONDECYT) Grant 3170826 (IR).


The authors want to thank Hannah Desmond for her help in editing the English for this article.

Conflicts of Interest

The authors declare no conflict of interest.


DNMT3BDNA methyltransferase 3B
MTSS1metastasis suppressor 1
ADAM12a disintegrin and metalloproteinase 12
PTENphosphatase and tensin homolog
TGF-βTransforming growth factor beta (β)
TGFRsTransforming growth factor b receptors
VEGFCvascular endothelial growth factor C
VEGFR3VEGF receptor 3
TIMPstissue inhibitor of metalloproteinases
MMPmatrix metalloproteinase
NF-κBnuclear factor kappa-beta
ECMextracellular matrix
EMTepithelial-mesenchymal transition
FAKFocal adhesion kinase
UPPubiquitination proteasome pathway
P-gpP-glycoprotein 1
ABCB1ATP Binding Cassette Subfamily B Member 1
ABCG2breast cancer resistance protein
PrPCcellular prion protein
TMEtumor microenvironment
CCL2/MCP-1chemokine (C-C motif) ligand 2/ monocyte chemoattractant protein 1
ROSreactive oxygen species
HIF-1Hypoxia Inducible Factor
FOLFIRICombination chemotherapy with Irinotecan plus 5-Fuorouracil/leucovorin
FOLFOXCombination chemotherapy with Oxaliplatin plus 5-Fuorouracil/leucovorin


  1. Mourão, P.A.; Pereira, M.S. Searching for alternatives to heparin: Sulfated fucans from marine invertebrates. Trends Cardiovasc. Med. 1999, 9, 225–232. [Google Scholar] [CrossRef]
  2. Iwamoto, R.; Mine, N.; Kawaguchi, T.; Minami, S.; Saeki, K.; Mekada, E. HB-EGF function in cardiac valve development requires interaction with heparan sulfate proteoglycans. Development 2010, 137, 2205–2214. [Google Scholar] [CrossRef] [Green Version]
  3. Nishino, T.; Nishioka, C.; Ura, H.; Nagumo, T. Isolation and partial characterization of a novel amino sugar-containing fucan sulfate from commercial Fucus vesiculosus fucoidan. Carbohydr. Res. 1994, 255, 213–224. [Google Scholar] [CrossRef]
  4. Barahona, T.; Chandía, N.P.; Encinas, M.V.; Matsuhiro, B.; Zúñiga, E.A. Food Hydrocolloids Antioxidant capacity of sulfated polysaccharides from seaweeds. A kinetic approach. Food Hydrocoll. 2011, 25, 529–535. [Google Scholar] [CrossRef]
  5. Li, B.; Lu, F.; Wei, X.; Zhao, R. Fucoidan: Structure and Bioactivity. Molecules 2008, 13, 1671–1695. [Google Scholar] [CrossRef] [Green Version]
  6. Kylin, H. Zur Biochemie der Meeresalgen. Z. für Physiol. Chem. 1913, 83, 171–197. [Google Scholar] [CrossRef]
  7. Springer, G.F.; Wurzel, H.A.; McNeal, G.M.; Ansell, N.J.; Doughty, M.F. Isolation of Anticoagulant Fractions from Crude Fucoidin. Exp. Biol. Med. 1957, 94, 404–409. [Google Scholar] [CrossRef]
  8. Kadam, S.; Alvarez, C.; Tiwari, B.; O’Donnell, C.P. Extraction of biomolecules from seaweeds. Seaweed Sustain. 2015, 243–269. [Google Scholar] [CrossRef]
  9. Chevolot, L.; Foucault, A.; Chaubet, F.; Kervarec, N.; Sinquin, C.; Fisher, A.-M.; Boisson-Vidal, C. Further data on the structure of brown seaweed fucans: Relationships with anticoagulant activity. Carbohydr. Res. 1999, 319, 154–165. [Google Scholar] [CrossRef]
  10. Percival, E.; McDowell, R.H. Chemistry and Enzymology of Marine Algal Polysaccharides, 1st ed.; Academic Press: Cambridge, MA, USA, 1967. [Google Scholar]
  11. Patankar, M.S.; Oehninger, S.; Barnett, T.; Williams, R.L.; Clark, G.F. A revised structure for fucoidan may explain some of its biological activities. J. Biol. Chem. 1993, 268, 21770–21776. [Google Scholar]
  12. Duarte, M.E.R.; A Cardoso, M.; Noseda, M.D.; Cerezo, A.S. Structural studies on fucoidans from the brown seaweed Sargassum stenophyllum. Carbohydr. Res. 2001, 333, 281–293. [Google Scholar] [CrossRef]
  13. Percival, E.E.; Jara, M.F.V.; Weigel, H. Carbohydrates of the brown seaweed lessonia nigrescens. Phytochem. 1983, 22, 1429–1432. [Google Scholar] [CrossRef]
  14. Chandía, N.; Matsuhiro, B. Characterization of a fucoidan from Lessonia vadosa (Phaeophyta) and its anticoagulant and elicitor properties. Int. J. Biol. Macromol. 2008, 42, 235–240. [Google Scholar] [CrossRef]
  15. Lim, S.J.; Aida, W.M.W.; Maskat, M.Y.; Latip, J.; Badri, K.H.; Hassan, O.; Yamin, B.M. Characterisation of fucoidan extracted from Malaysian Sargassum binderi. Food Chem. 2016, 209, 267–273. [Google Scholar] [CrossRef]
  16. Bilan, M.I.; Grachev, A.A.; Shashkov, A.S.; Nifantiev, N.E.; Usov, A.I. Structure of a fucoidan from the brown seaweed Fucus serratus L. Carbohydr. Res. 2006, 341, 238–245. [Google Scholar] [CrossRef]
  17. Usoltseva, R.V.; Anastyuk, S.D.; Ishina, I.; Isakov, V.V.; Zvyagintseva, T.N.; Thinh, P.D.; Zadorozhny, P.A.; Dmitrenok, P.S.; Ermakova, S.P. Structural characteristics and anticancer activity in vitro of fucoidan from brown alga Padina boryana. Carbohydr. Polym. 2018, 184, 260–268. [Google Scholar] [CrossRef]
  18. Chen, L.-M.; Liu, P.-Y.; Chen, Y.-A.; Tseng, H.-Y.; Shen, P.-C.; Hwang, P.-A.; Hsu, H.-L. Oligo-Fucoidan prevents IL-6 and CCL2 production and cooperates with p53 to suppress ATM signaling and tumor progression. Sci. Rep. 2017, 7, 11864. [Google Scholar] [CrossRef] [Green Version]
  19. Chen, A.; Lan, Y.; Liu, J.; Zhang, F.; Zhang, L.; Li, B.; Zhao, X. The structure property and endothelial protective activity of fucoidan from Laminaria japonica. Int. J. Biol. Macromol. 2017, 105, 1421–1429. [Google Scholar] [CrossRef]
  20. Synytsya, A.; Kim, W.-J.; Kim, S.-M.; Pohl, R.; Synytsya, A.; Kvasnicka, F.; Čopíková, J.; Park, Y.I. Structure and antitumour activity of fucoidan isolated from sporophyll of Korean brown seaweed Undaria pinnatifida. Carbohydr. Polym. 2010, 81, 41–48. [Google Scholar] [CrossRef]
  21. Fletcher, H.; Biller, P.; Ross, A.; Adams, J. The seasonal variation of fucoidan within three species of brown macroalgae. Algal Res. 2017, 22, 79–86. [Google Scholar] [CrossRef] [Green Version]
  22. Vilela-Silva, A.C.E.S.; Alves, A.-P.; Valente, A.P.; Vacquier, V.D.; Mourão, P.A. Structure of the sulfated -L-fucan from the egg jelly coat of the sea urchin Strongylocentrotus franciscanus: Patterns of preferential 2-O- and 4-O-sulfation determine sperm cell recognition. Glycobiology 1999, 9, 927–933. [Google Scholar] [CrossRef] [Green Version]
  23. Kariya, Y.; Mulloy, B.; Imai, K.; Tominaga, A.; Kaneko, T.; Asari, A.; Suzuki, K.; Masuda, H.; Kyogashima, M.; Ishii, T. Isolation and partial characterization of fucan sulfates from the body wall of sea cucumber Stichopus japonicus and their ability to inhibit osteoclastogenesis. Carbohydr. Res. 2004, 339, 1339–1346. [Google Scholar] [CrossRef]
  24. Chang, Y.; Hu, Y.; Yu, L.; McClements, D.J.; Xu, X.; Liu, G.; Xue, C. Primary structure and chain conformation of fucoidan extracted from sea cucumber Holothuria tubulosa. Carbohydr. Polym. 2016, 136, 1091–1097. [Google Scholar] [CrossRef] [Green Version]
  25. Jiang, W.G.; Sanders, A.J.; Katoh, M.; Ungefroren, H.; Gieseler, F.; Prince, M.; Thompson, S.K.; Zollo, M.; Spano, D.; Dhawan, P.; et al. Tissue invasion and metastasis: Molecular, biological and clinical perspectives. Semin. Cancer Biol. 2015, 35, 244–275. [Google Scholar] [CrossRef]
  26. Gupta, G.P.; Massagué, J. Review Cancer Metastasis: Building a Framework. Cell 2006, 127, 679–695. [Google Scholar] [CrossRef] [Green Version]
  27. Lambert, A.W.; Pattabiraman, D.R.; Weinberg, R.A. Review Emerging Biological Principles of Metastasis. Cell 2016, 168, 670–691. [Google Scholar] [CrossRef] [Green Version]
  28. Fontebasso, Y.; Dubinett, S.M. Drug Development for Metastasis Prevention. Crit. Rev. Oncog. 2015, 20, 449–473. [Google Scholar] [CrossRef]
  29. Alizadeh, A.M.; Shiri, S.; Farsinejad, S. Metastasis review: From bench to bedside. Tumor Biol. 2014, 35, 8483–8523. [Google Scholar] [CrossRef]
  30. Yang, J.; Weinberg, R.A. Review Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis. Dev. Cell. 2008, 14, 818–829. [Google Scholar] [CrossRef] [Green Version]
  31. Zhang, X.; Pei, Z.; Ji, C.; Zhang, X.; Xu, J.; Wang, J. Chapter 15: Novel Insights into the Role of the Cytoskeleton in Cancer. In Cytoskeleton-Structure, Dynamics, Function and Disease; IntechOpen: London, UK, 2017; pp. 299–313. [Google Scholar]
  32. Coombe, D.R.; Parish, C.R.; Ramshaw, I.A.; Snowden, J.M. Analysis of the inhibition of tumour metastasis by sulphated polysaccharides. Int. J. Cancer 1987, 39, 82–88. [Google Scholar] [CrossRef]
  33. He, X.; Xue, M.; Jiang, S.; Li, W.; Yu, J.; Xiang, S. Fucoidan Promotes Apoptosis and Inhibits EMT of Breast Cancer Cells. Biol. Pharm. Bull. 2019, 42, 442–447. [Google Scholar] [CrossRef] [Green Version]
  34. Hsu, H.-Y.; Lin, T.-Y.; Hwang, P.-A.; Tseng, L.-M.; Chen, R.-H.; Tsao, S.-M.; Hsu, J. Fucoidan induces changes in the epithelial to mesenchymal transition and decreases metastasis by enhancing ubiquitin-dependent TGF receptor degradation in breast cancer. Carcinogenesis 2012, 34, 874–884. [Google Scholar] [CrossRef]
  35. Hsu, H.-Y.; Lin, T.-Y.; Wu, Y.-C.; Tsao, S.-M.; Hwang, P.-A.; Shih, Y.-W.; Hsu, J. Fucoidan inhibition of lung cancer in vivo and in vitro: Role of the Smurf2-dependent ubiquitin proteasome pathway in TGFβ receptor degradation. Oncotarget 2014, 5, 7870–7885. [Google Scholar] [CrossRef] [Green Version]
  36. Yan, M.-D.; Lai, G.-M.; Chow, J.-M.; Chang, C.-L.; Hwang, P.-A.; Chuang, S.-E.; Whang-Peng, J.; Lai, G.-M. Fucoidan Elevates MicroRNA-29b to Regulate DNMT3B-MTSS1 Axis and Inhibit EMT in Human Hepatocellular Carcinoma Cells. Mar. Drugs 2015, 13, 6099–6116. [Google Scholar] [CrossRef] [Green Version]
  37. Wu, S.; Yan, M.; Wu, A.T.H.; Yuan, K.S.; Liu, S.H. Brown Seaweed Fucoidan Inhibits Cancer Progression by Dual Regulation of mir-29c / ADAM12 and miR-17-5p/PTEN Axes in Human Breast Cancer Cells. J. Cancer 2016, 7, 2408–2419. [Google Scholar] [CrossRef] [Green Version]
  38. Pan, T.; Li, L.; Zhang, J.; Yang, Z.; Shi, D.; Yang, Y. Antimetastatic Effect of Fucoidan-Sargassum against Liver Cancer Cell Invadopodia Formation via Targeting Integrin α V β 3 and Mediating α V β 3 / Src / E2F1 Signaling. J. Cancer 2019, 10, 4777–4792. [Google Scholar] [CrossRef]
  39. Atashrazm, F.; Lowenthal, R.; Woods, G.M.; Holloway, A.; Dickinson, J. Fucoidan and Cancer: A Multifunctional Molecule with Anti-Tumor Potential. Mar. Drugs 2015, 13, 2327–2346. [Google Scholar] [CrossRef] [Green Version]
  40. Wang, P.; Liu, Z.; Liu, X.; Teng, H.; Zhang, C.; Hou, L.; Zou, X. Anti-Metastasis Effect of Fucoidan from Undaria pinnatifida Sporophylls in Mouse Hepatocarcinoma Hca-F Cells. PLoS ONE 2014, 9, e106071. [Google Scholar] [CrossRef] [Green Version]
  41. Han, Y.S.; Lee, J.; Lee, S. Fucoidan inhibits the migration and proliferation of HT-29 human colon cancer cells via the phosphoinositide-3 kinase / Akt / mechanistic target of rapamycin pathways. Mol. Med. Rep. 2015, 12, 3446–3452. [Google Scholar] [CrossRef]
  42. Hsu, W.; Lin, M.; Kuo, T.; Chou, C. Fucoidan from luminaria japonica exerts antitumor effects on angiogenesis and micrometastasis in triple-negative breast cancer cells. Int. J. Biol Macromol. 2020, 149, 600–608. [Google Scholar] [CrossRef]
  43. Teng, H.; Yang, Y.; Wei, H.; Liu, Z.; Liu, Z.; Ma, Y.; Gao, Z.; Hou, L.; Zou, X. Fucoidan Suppresses Hypoxia-Induced Lymphangiogenesis and Lymphatic Metastasis in Mouse Hepatocarcinoma. Mar. Drugs 2015, 13, 3514–3530. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Soisuwan, S.; Warisnoicharoen, W. Eco-Friendly Synthesis of Fucoidan-Stabilized Gold Nanoparticles Kriengsak Lirdprapamongkol and 3 Jisnuson Svasti Pharmaceutical Technology (International Program), Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences. Am. J. Appl. Sci. 2010, 7, 1038–1042. [Google Scholar]
  45. Cho, Y.; Yoon, J.-H.; Yoo, J.-J.; Lee, M.; Lee, D.H.; Cho, E.J.; Lee, J.-H.; Yu, S.J.; Kim, Y.J.; Kim, C.Y. Fucoidan protects hepatocytes from apoptosis and inhibits invasion of hepatocellular carcinoma by up-regulating p42/44 MAPK-dependent NDRG-1/CAP43. Acta Pharm. Sin. B 2015, 5, 544–553. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Sun, J.; Sun, J.; Song, B.; Zhang, L.; Shao, Q.; Liu, Y.; Yuan, D.; Zhang, Y.; Qu, X. Fucoidan inhibits CCL22 production through NF-κB pathway in M2 macrophages: A potential therapeutic strategy for cancer. Sci. Rep. 2016, 6, 35855. [Google Scholar] [CrossRef]
  47. Hsu, H.; Lin, T.; Hu, C.; Ta, D.; Shu, F.; Lu, M. Fucoidan upregulates TLR4/CHOP-mediated caspase-3 and PARP activation to enhance cisplatin-induced cytotoxicity in human lung cancer cells. Cancer Lett. 2018, 432, 112–120. [Google Scholar] [CrossRef]
  48. Qiu, W.L.; Tseng, A.J.; Hsu, H.Y.; Hsu, W.H.; Lin, Z.H.; Hua, W.J.L.T. Fucoidan increased the sensitivity to gefitinib in lung cancer cells correlates with reduction of TGFβ-mediated Slug expression. Int. J. Biol. Macromol. 2020, 153, 796–805. [Google Scholar] [CrossRef]
  49. Li, W.; Xue, D.; Xue, M.; Zhao, J.; Liang, H.U.I.; Liu, Y.; Sun, T. Fucoidan inhibits epithelial-to-mesenchymal transition via regulation of the HIF-1 α pathway in mammary cancer cells under hypoxia. Oncol. Lett. 2019, 18, 330–338. [Google Scholar] [CrossRef]
  50. Burney, M.; Mathew, L.; Gaikwad, A.; Nugent, E.K.; Gonzalez, A.O.; Smith, J.A. Evaluation Fucoidan Extracts From Undaria pinnatifida and Fucus vesiculosus in Combination With Anticancer Drugs in Human Cancer Orthotopic Mouse Models. Integr. Cancer Ther. 2017, 17, 755–761. [Google Scholar] [CrossRef] [Green Version]
  51. Pawar, V.K.; Singh, Y.; Sharma, K.; Shrivastav, A.; Sharma, A.; Singh, A.; Meher, J.G.; Singh, P.; Raval, K.; Kumar, A.; et al. Improved chemotherapy against breast cancer through immunotherapeutic activity of fucoidan decorated electrostatically assembled nanoparticles bearing doxorubicin. Int. J. Biol. Macromol. 2019, 122, 1100–1114. [Google Scholar] [CrossRef]
  52. Zhang, Y.; Zhao, D.; Yang, S.; Yao, H.; Li, M.; Zhao, C.; Zhang, J.; Xu, G.-T.; Li, H.; Wang, F. Protective Effects of Fucoidan on Epithelial-Mesenchymal Transition of Retinal Pigment Epithelial Cells and Progression of Proliferative Vitreoretinopathy. Cell. Physiol. Biochem. 2018, 46, 1704–1715. [Google Scholar] [CrossRef] [Green Version]
  53. Kim, I.H.; Kwon, M.J.; Nam, T.J. Differences in cell death and cell cycle following fucoidan treatment in high-density HT-29 colon cancer cells. Mol. Med. Rep. 2017, 15, 4116–4122. [Google Scholar] [CrossRef] [Green Version]
  54. Yun, C.W.; Yun, S.; Lee, J.H.; Han, Y.-S.; Yoon, Y.M.; An, D.; Lee, S.H. Silencing Prion Protein in HT29 Human Colorectal Cancer Cells Enhances Anticancer Response to Fucoidan. Anticancer. Res. 2016, 36, 4449–4458. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Hsu, H.-Y.; Hwang, P.-A. Clinical applications of fucoidan in translational medicine for adjuvant cancer therapy. Clin. Transl. Med. 2019, 8, 15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Shin, S.-W.; Jung, W.; Choi, C.; Kim, S.-Y.; Son, A.; Kim, H.; Lee, N.; Park, H.C. Fucoidan-Manganese Dioxide Nanoparticles Potentiate Radiation Therapy by Co-Targeting Tumor Hypoxia and Angiogenesis. Mar. Drugs 2018, 16, 510. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Rui, X.; Pan, H.-F.; Shao, S.-L.; Xu, X.-M. Anti-tumor and anti-angiogenic effects of Fucoidan on prostate cancer: Possible JAK-STAT3 pathway. BMC Complement. Altern. Med. 2017, 17, 378. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Zhang, Z.; Teruya, K.; Yoshida, T.; Eto, H.; Shirahata, S. Fucoidan Extract Enhances the Anti-Cancer Activity of Chemotherapeutic Agents in MDA-MB-231 and MCF-7 Breast Cancer Cells. Mar. Drugs 2013, 11, 81–98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Thakur, V.; Lu, J.; Roscilli, G.; Aurisicchio, L.; Cappelletti, M. The natural compound fucoidan from New Zealand Undaria pinnatifida synergizes with the ERBB inhibitor lapatinib enhancing melanoma growth inhibition Fucoidan extracted from New Zealand. Oncotarget 2017, 8, 17887–17896. [Google Scholar] [CrossRef]
  60. Tsai, H.-L.; Tai, C.-J.; Huang, C.-W.; Chang, F.-R.; Wang, J.-Y. Efficacy of Low-Molecular-Weight Fucoidan as a Supplemental Therapy in Metastatic Colorectal Cancer Patients: A Double-Blind Randomized Controlled Trial. Mar. Drugs 2017, 15, 122. [Google Scholar] [CrossRef] [Green Version]
  61. Foley, S.; Szegezdi, E.; Mulloy, B.; Samali, A.; Tuohy, M.G. An Unfractionated Fucoidan fromAscophyllum nodosum: Extraction, Characterization, and Apoptotic Effects in Vitro. J. Nat. Prod. 2011, 74, 1851–1861. [Google Scholar] [CrossRef]
  62. Riou, D.; Colliec-Jouault, S.; Du Sel, D.P.; Bosch, S.; Siavoshian, S.; Le Bert, V.; Tomasoni, C.; Sinquin, C.; Durand, P.; Roussakis, C. Antitumor and antiproliferative effects of a fucan extracted from ascophyllum nodosum against a non-small-cell bronchopulmonary carcinoma line. Anticancer Res. 1996, 16, 1213–1218. [Google Scholar]
  63. Deslandes, E.; Pondaven, P.; Auperin, T.; C, C.R.; Guezennec, J.; Stiger-Pouvreau, V.; Payri, C. Preliminary study of the in vitro antiproliferative effect of a hydroethanolic extract from the subtropical seaweed Turbinaria ornata (Turner) J. Agardh on a human non-small-cell bronchopulmonary carcinoma line (NSCLC-N6). Environ. Biol. Fishes 2000, 12, 257–262. [Google Scholar] [CrossRef]
  64. Thanh, T.T.T.; Tran, V.T.T.; Yuguchi, Y.; Bui, L.M.; Nguyen, T.T. Structure of Fucoidan from Brown Seaweed Turbinaria ornata as Studied by Electrospray Ionization Mass Spectrometry (ESIMS) and Small Angle X-ray Scattering (SAXS) Techniques. Mar. Drugs 2013, 11, 2431–2443. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Lim, S.J.; Mustapha, W.A.W.; Schiehser, S.; Rosenau, T.; Böhmdorfer, S. Structural elucidation of fucoidan from Cladosiphon okamuranus (Okinawa mozuku). Food Chem. 2019, 272, 222–226. [Google Scholar] [CrossRef] [PubMed]
  66. Kang, S.; Kang, K.; Chae, A.; Kim, Y.-K.; Jang, H.; Min, D.-H. Fucoidan-coated coral-like Pt nanoparticles for computed tomography-guided highly enhanced synergistic anticancer effect against drug-resistant breast cancer cells. Nanoscale 2019, 11, 15173–15183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. National Cancer Institute Home Page. Types of Cancer Treatment. Available online: (accessed on 3 April 2020).
  68. Alfarouk, K.; Stock, C.-M.; Taylor, S.; Walsh, M.; Muddathir, A.K.; Verduzco, D.; Bashir, A.; Mohammed, O.Y.; ElHassan, G.O.; Harguindey, S.; et al. Resistance to cancer chemotherapy: Failure in drug response from ADME to P-gp. Cancer Cell Int. 2015, 15, 71. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Shi, W.-J.; Gao, J.-B. Molecular mechanisms of chemoresistance in gastric cancer. World J. Gastrointest. Oncol. 2016, 8, 673–681. [Google Scholar] [CrossRef]
  70. Sun, S.; Cai, J.; Yang, Q.; Zhu, Y.; Zhao, S.; Wang, Z. Prognostic Value and Implication for Chemotherapy Treatment of ABCB1 in Epithelial Ovarian Cancer: A Meta-Analysis. PLoS ONE 2016, 11, e0166058. [Google Scholar] [CrossRef]
  71. Balch, C.; Huang, T.H.-M.; Brown, R.; Nephew, K.P. The epigenetics of ovarian cancer drug resistance and resensitization. Am. J. Obstet. Gynecol. 2004, 191, 1552–1572. [Google Scholar] [CrossRef]
  72. Niero, E.L.; Rocha-Sales, B.; Lauand, C.; Cortez, B.A.; De Souza, M.M.; Rezende-Teixeira, P.; Urabayashi, M.; Martens, A.A.; Neves, J.H.; Machado-Santelli, G.M. The multiple facets of drug resistance: One history, different approaches. J. Exp. Clin. Cancer Res. 2014, 33, 37. [Google Scholar] [CrossRef] [Green Version]
  73. Szakács, G.; Jakab, K.; Antal, F.; Sarkadi, B. Diagnostics of multidrug resistance in cancer. Pathol. Oncol. Res. 1998, 4, 251–257. [Google Scholar]
  74. Rabik, C.; Dolan, M.E. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat. Rev. 2006, 33, 9–23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Johnstone, R.W.; Ruefli, A.A.; Tainton, K.M.; Smyth, M.J. A Role for P-Glycoprotein in Regulating Cell Death. Leuk. Lymphoma 2000, 38, 1–11. [Google Scholar] [CrossRef] [PubMed]
  76. Harfe, B.D. MicroRNAs in vertebrate development. Curr. Opin. Genet. Dev. 2005, 15, 410–415. [Google Scholar] [CrossRef] [PubMed]
  77. Hwang, W.; Hwang, Y.; Lee, S.; Lee, D.S. Rule-based multi-scale simulation for drug effect pathway analysis. BMC Med. Inform. Decis. Mak. 2013, 13, S4. [Google Scholar] [CrossRef] [Green Version]
  78. Galluzzi, L.; Senovilla, L.; Vitale, I.; Michels, J.; Martins, I.; Kepp, O.; Castedo, M.; Kroemer, G. Molecular mechanisms of cisplatin resistance. Oncogene 2011, 31, 1869–1883. [Google Scholar] [CrossRef] [Green Version]
  79. Lee, J.H.; Yun, C.W.; Lee, S.H. Cellular Prion Protein Enhances Drug Resistance of Colorectal Cancer Cells via Regulation of a Survival Signal Pathway. Biomol. Ther. 2017, 26, 313–321. [Google Scholar] [CrossRef]
  80. Jones, V.S.; Huang, R.-Y.; Chen, L.-P.; Chen, Z.-S.; Fu, L.; Huang, R.-P. Cytokines in cancer drug resistance: Cues to new therapeutic strategies. Biochim. Biophys. Acta (BBA)-Bioenerg. 2016, 1865, 255–265. [Google Scholar] [CrossRef] [Green Version]
  81. Aldinucci, D.; Colombatti, A. The Inflammatory Chemokine CCL5 and Cancer Progression. Mediat. Inflamm. 2014, 2014, 292376. [Google Scholar] [CrossRef] [Green Version]
  82. Salgado, R.; Junius, S.; Benoy, I.; Van Dam, P.A.; Vermeulen, P.; Van Marck, E.; Huget, P.; Dirix, L. Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int. J. Cancer 2002, 103, 642–646. [Google Scholar] [CrossRef]
  83. Bar-Eli, M. Role of interleukin-8 in tumor growth and metastasis of human melanoma. Pathobiology 1999, 67, 12–18. [Google Scholar] [CrossRef]
  84. Benoy, I.; Salgado, R.; Van Dam, P.A.; Geboers, K.; Van Marck, E.; Scharpe, S.; Vermeulen, P.B.; Dirix, L. Increased Serum Interleukin-8 in Patients with Early and Metastatic Breast Cancer Correlates with Early Dissemination and Survival. Clin. Cancer Res. 2004, 10, 7157–7162. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Kornienko, A.E.; Guenzl, P.M.; Barlow, D.P.; Pauler, F.M. Gene regulation by the act of long non-coding RNA transcription. BMC Biol. 2013, 11, 59. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Schneider, G.; Salcedo, R.; Welniak, L.; Howard, O.; Murphy, W. The diverse role of chemokines in tumor progression: Prospects for intervention (Review). Int. J. Mol. Med. 2001, 8, 235–244. [Google Scholar] [CrossRef] [PubMed]
  87. Carreno-Gomez, B.; Duncan, R. Compositions with Enhanced Oral Bioavailability. U.S. Patent 20030211072A1, 13 November 2003. [Google Scholar]
  88. Hwang, P.-A.; Lin, X.-Z.; Kuo, K.-L.; Hsu, F.-Y. Fabrication and Cytotoxicity of Fucoidan-Cisplatin Nanoparticles for Macrophage and Tumor Cells. Mater. 2017, 10, 291. [Google Scholar] [CrossRef] [Green Version]
  89. Tocaciu, S.; Oliver, L.J.; Lowenthal, R.M.; Peterson, G.M.; Patel, R.; Shastri, M.; McGuinness, G.; Olesen, I.; Fitton, J.H. The Effect of Undaria pinnatifida Fucoidan on the Pharmacokinetics of Letrozole and Tamoxifen in Patients With Breast Cancer. Integr. Cancer Ther. 2016, 17, 99–105. [Google Scholar] [CrossRef] [Green Version]
  90. Ikeguchi, M.; Yamamoto, M.; Arai, Y.; Maeta, Y.; Ashida, K.; Katano, K.; Miki, Y.; Kimura, T. Fucoidan reduces the toxicities of chemotherapy for patients with unresectable advanced or recurrent colorectal cancer. Oncol. Lett. 2011, 2, 319–322. [Google Scholar] [CrossRef]
  91. Nagamine, T.; Kadena, K.; Tomori, M.; Nakajima, K.; Iha, M. Activation of NK cells in male cancer survivors by fucoidan extracted from Cladosiphon okamuranus. Mol. Clin. Oncol. 2019, 12, 81–88. [Google Scholar] [CrossRef] [Green Version]
  92. Takahashi, H.; Kawaguchi, M.; Kitamura, K.; Narumiya, S.; Kawamura, M.; Tengan, I.; Nishimoto, S.; Hanamure, Y.; Majima, Y.; Tsubura, S.; et al. An Exploratory Study on the Anti-inflammatory Effects of Fucoidan in Relation to Quality of Life in Advanced Cancer Patients. Integr. Cancer Ther. 2017, 17, 282–291. [Google Scholar] [CrossRef] [Green Version]
  93. Nishimoto, S. Clinical Improvement in Cancer Patients through Integrated Medicine, Mainly Using Low Molecular Weight Fucoidan Supplements. J. Int. Soc. Life Inf. Sci. 2015, 33, 25–37. [Google Scholar]
Figure 1. Comparison between fucoidan and glycosaminoglycan structures. (A) Structure of fucoidan from the brown alga Fucus vesiculosus and (B) structure of chondroitin sulphate. It is important to remark the similarity in the sugar skeleton and the presence of sulphate groups (red) in both structures. “R” represents a fucose subunit without sulphate.
Figure 1. Comparison between fucoidan and glycosaminoglycan structures. (A) Structure of fucoidan from the brown alga Fucus vesiculosus and (B) structure of chondroitin sulphate. It is important to remark the similarity in the sugar skeleton and the presence of sulphate groups (red) in both structures. “R” represents a fucose subunit without sulphate.
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Figure 2. Summary of the main signaling pathways involved in the fucoidan function during the processes of metastasis and drug resistance.
Figure 2. Summary of the main signaling pathways involved in the fucoidan function during the processes of metastasis and drug resistance.
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Table 1. Sources, characteristics and effects of fucoidans on the metastatic and drug-resistant phenotype of cancer models.
Table 1. Sources, characteristics and effects of fucoidans on the metastatic and drug-resistant phenotype of cancer models.
SourceFucoidan StructureCancer Type/ModelEffects/PathwaysRefs
Fucus vesiculosusThis fucoidan has a central core formed by α-L-fucose (1,3)-linked, sulphated at C4. In addition, several branching points (every two or three fucose residues) were present in α-(1,2) or α-(1,4)-linked, on the main chain.Hepatocellular carcinoma (HCC)[45]
In vitro
Huh-7 and SNU-761 cell lines
Effects on metastasis by avoiding invasion
↑p42/44MAPK-dependent NDRG-1/CAP43
↑p42/44 MAPK-dependent VMP-1
In vivo
Distant metastasis model in C3H mice
Effects on metastasis by avoiding invasion
↓MMPs (MMP-2)
In vitro
MHCC-97H cell line
Nanoparticle drug resistance
fucoidan downregulate chemokines and cytokines involved in chemoresistance
Lung cancer[35]
In vitro
NSCLC CL1-5 human cells
A549 human cells
LLC1 mouse cells
Effects on metastasis by avoiding migration and proliferation
In vivo
Drug resistance and Combined therapy
↑ Cisplatin cytotoxicity
↑Caspase 3, PARP and apoptosis
Lung cancer cell line
In vitro
Synergize with gefitinib and ↑apoptosis[48]
Breast cancer[34]
In vitro
MDA-MB-231 and MCF-7 human breast cancer cells
In vivo
4T1 mouse breast adenocarcinoma
Effects on metastasis by avoiding EMT
↑E-Cadherin, ↑γ-Catenin
In vitro
MDA-MB-231 cells
Effects on metastasis by avoiding EMT
↓N-Cadherin and ↓vimentin
↑ZO-1, ↑E-Cadherin
↓Nuclear translocation of HIF-1α
In vitro
MCF-7 and ZR-75
In vivo
Mouse model
Combined therapy
increase effect Tamoxifen
In vitro
MDA-MB-231 human breast cancer cells, 4T1 mouse breast cells and J774.1A mouse macrophage cells.
In vivo
BALB/c mice
Nanoparticle combined therapy
↑ immunostimulatory activity and increase doxorubicin effect
Proliferative vitreoretinopathy (PVR)[52]
In vitro
Human primary RPE cells
In vivo
PVR model in rabbits
Effects on metastasis by avoiding EMT
↓TGF-β1-induced SMAD2/3 phosphorylation
↓α-SMA and fibronectin
Colorectal cancer (CRC)[41,53]
In vitro
HT29 human cells
Effects on proliferation
↓Cyclin D1/E and ↓CDK2/4
Effects on apoptosis
↑BAX, ↑Caspase-3, ↑PARP1
In vitro
HT29 human colon cancer cells
Effects on metastasis by avoiding migration
drug resistance by effect in P38 and JNK pathways
Drug resistance related
decrease prion protein and decrease cell survival and could
HCT-8 human ileocecal
In vitro
Combined therapy
↑cytotoxicity than those treated with cisplatin alone
Pancreatic cancer[56]
In vitro
AsPC-3 and BxPC-3 human pancreatic cancer cell lines
Effects on metastasis by avoiding hypoxia and angiogenesis
↓Hypoxia induced radioresistance
↓Tumor growth and angiogenesis
In vivo
Combined therapy
Prostate cancer[57]
In vitro
DU-145 human cells
In vivo
Effects on metastasis by avoiding angiogenesis
↓CD31 and CD105
↓p-JAK and p-STAT3
↓VEGF, Bcl-xL, Cyclin D1
Cladosiphon navae-caledoniaeLow molecular weight fraction (72%, MW < 500 Da) and non-digested fractions (less than 28%, peak MW: 800 kDa).
Fucose (73%), xylose (12%) and mannose (7%). The ratio of sulphation was 14.5%.
Breast cancer[58]
In vitro
ER-positive MCF-7 cells
ER-negative MDA-MB-231 cells
Effects on metastasis and apoptosis
↓p-ERK and ↓AKT in MDA-MB-231 cells
↑p-ERK in MCF-7 cells
↑IC-ROS and ↓GSH in both cell lines
Effects on drug resistance
↑cisplatin, tamoxifen and paclitaxel efficacy
↓Cell growth, ↑apoptosis
↓Bcl-xL, ↓Mcl-1
Combined therapy
Undaria pinnatifidaThis sulphated galactofucan is composed of:
Galactose 44.6% and Fucose 50.9%.
Xylose (4.2%)
Mannose (0.3%), uronic acids were not detected.
A significant number of O-acetyl groups
Hepatocellular carcinoma (HCC)[20,40,43]
In vitro
Hca-F cell line
Effects on metastasis
↓HGF/c-MET, cyclin D1.
↓PI3K, p-AKT, p-ERK 1/2, and NF-κB
Effects on metastasis by avoiding hypoxia
↓p-PI3K, ↓p-AKT, ↓p-mTOR
↓MMP-2, ↓MMP-9
In vivo
Hca-F cells were inoculated subcutaneously into the footpads of the mice
Effects on metastasis by deregulating adhesion/invasion
↓ L-Selectin
Effects on metastasis by avoiding lymph angiogenesis and lymphatic infiltration
Melanoma cancer
In vitro
WM266-4, WM115 (mutated BRAF), SKMEL2 (RAS mutated), MeWo and FEMX (wild type)
Effects on drug resistance and combined therapy
Fucoidan increase Lapatinib (ERBB inhibitor) effect in drug resistance cell
Breast cancer
In vitro
MCF-7 and ZR-75
In vivo
Mouse model
Combined therapy
Increase effect in Tamoxifen treatment
Sargassum hemiphyllum Colorectal cancer (CRC)[60]
Double-Blind Randomized Controlled TrialFucoidan as a supplemental therapy to chemotarget agents in patients with metastatic CRC
Hepatocellular carcinoma (HCC)[36]
In vitro
Huh6, Huh7, SK-Hep1 and HepG2 human cells.
Effects on metastasis by avoiding EMT
↑miR-29b, ↓DNMT3B, ↑MTSS1
↑E-Cadherin, ↓N-Cadherin
↑TIMP-1, ↓MMP-2/9
Breast Cancer[37]
In vitro
MCF-10A, MCF-7
Effects on metastasis by avoiding migration and invasion
↑miR-29c, ↓ADAM12
↓miR-17-5p, ↑PTEN
MDA-MB-231 human cells.Effects on metastasis by avoiding EMT
↑E-Cadherin, ↓N-Cadherin
Ascophyllum nodosumThis fucoidan is composed of fucose (52.1%), galactose (6.1%), glucose (21.3%), and xylose (16.5%). Sulphate content is 19%. Two main size fractions (47 and 420 kDa).NSCLC (Lung cancer)[61,62]
In vitro
Effects on cell cycle arrest
In vivo
Turbinaria ornateThe results showed that the fucoidan has a sulphate content of 25.6% and is mainly composed of fucose and galactose residues (Fuc:Gal ≈ 3:1). The fucoidan has a backbone of 3-linked α-L-Fucose residues with branches, →4)-Galp(1→ at C-4 of the fucan chain. Sulphate groups are attached mostly at C-2 and sometimes at C-4 of both fucose and galactose residues.NSCLC (Lung cancer)[63,64]
In vitro
Effects on cell cycle arrest
Cladosiphon okamuranusThe fucoidan is composed of 70.13 ± 0.22 wt% fucose and 15.16 ± 1.17 wt% sulphate. Other minor monosaccharides are D-xylose, D-galactose, D-mannose, D-glucose, D-arabinose, D-rhamnose and D-glucuronic acid. Linkage analysis revealed that fucopyranoside units along the backbone are linked, through α-1,3-glycosidic bonds, with fucose branching at C-2, and one sulphate group at C-4 per every three fucose units, i.e. the structure of fucoidan from Japanese Cladosiphon okamuranus is [→3)-α-fuc(1→]0.52[→3)-α-fuc-4-OSO3-(1→]0.33[→2)-α-fuc]0.14.Breast cancer[65,66]
In vitro
(drug resistant human breast cancer cell line)
Combination therapy
(Synergistic effect doxorubicin and photothermal nanocarrier)
↑doxorubicin delivery
↑ morphology-control in Pt-nanoparticles
In vivo
Sargassum fusiformeThe fucoidan is composed of fucose, xylose, galactose, mannose, glucuronic acid, and 20.8% sulphate. The 17 sulphate groups are attached to diverse positions of fucose, xylose, mannose, and galactose residues. The backbone consists of alternate 1, 2-linked α-D-Mannose and 1, 4-linked β-D-GlcpAHepatocellular carcinoma (HCC)[38]
In vitro
SMMC-7721, Huh7 and HCCLM3 cells
Effects on metastasis by avoiding migration and invasion
In vivo
↓Invadopodia-related proteins (Src, Cortactin, N-WASP, ARP3, CDC42, MMP2, MT1-MMP)
↓Integrin αVβ3
α-SMA: α-smooth muscle actin. CDK: Cyclin dependent kinase. CRC: Colorectal cancer. CTGF: Connective tissue growth factor. EMT. Epithelial-mesenchymal transition. ER: Estrogen receptor. FAK: Focal adhesion kinase. FE: Fucoidan extract. GSH: Glutathione. HCC: Hepatocellular carcinoma. HGF: hepatocyte growth factor. CRC: colorectal cancer. NSCLC: Non-small-cells human bronchopulmonary carcinoma. IC-ROS: Intra cellular reactive oxygen species. LMWF: Low molecular weight fucoidan. MMP: Matrix metalloproteinase. NDRG: N-myc downstream-regulated gene. PTEN: phosphatase and tensin homolog. PVR: Proliferative vitreoretinopathy. ROS: Oxygen reactive species. RPE: Retinal pigment epithelial. TGFR: Transforming growth factor-b receptor. TIMP: Tissue inhibitor of metalloproteinase. VEGF: Vascular endothelial growth factor. VMP: vacuole membrane protein.
Table 2. Fucoidans tested in clinical trials.
Table 2. Fucoidans tested in clinical trials.
SourceCancer Type (No Patients)Fucoidan DosageEffectsRefs
Undaria pinnatifidaBreast cancer
(20 patients)
Capsule of 500 mg twice a day for 3 weeksLetrozole (n = 10) or Tamoxifen (n = 10) co-administration with fucoidan no decrease drugs in steady-state plasma and was well tolerated.[89]
Sargassum hemiphyllumColorectal cancer
(54 patients)
4 g twice a day
for 6 months
Supplemental therapy, fucoidan combined with FOLFIRI chemotherapy plus Bevacizumab improved disease control rate.[60]
Cladosiphon okamuranusUnresectable advanced or recurrent cases of colorectal cancer
(20 patients).
4.05 g for dayDecreases toxicity of chemotherapy FOLFOX or FOLFIRI.[90]
Survivors of diverse cancer types
(11 patients).
1.5 g twice a day
for 6 months
Activation of NK cells in male cancer survivors[91]
Advanced cases of several types of cancer
(20 patients).
4 g for day
for 4 weeks
Anti-inflammatory effect, decreases IL-1β, IL-6 and TNF-α[92]
Nemacystis decipiensCervical cancer
(1 case study)
Kidney cancer
(1 case study)
Breast cancer
(1 case study)
200 mL/day
60 mLx3L/day
200 mL/day
No concluded information [93]
FOLFIRI: Combination chemotherapy with Irinotecan plus 5-Fuorouracil/leucovorin; FOLFOX: Combination chemotherapy with Oxaliplatin plus 5-Fuorouracil/leucovorin; NK: Natural Killer; IL-1β: Interleukin 1-β; IL-6: Interleukin 6; TNF-α: Tumor Necrosis Factor-α.

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Reyes, M.E.; Riquelme, I.; Salvo, T.; Zanella, L.; Letelier, P.; Brebi, P. Brown Seaweed Fucoidan in Cancer: Implications in Metastasis and Drug Resistance. Mar. Drugs 2020, 18, 232.

AMA Style

Reyes ME, Riquelme I, Salvo T, Zanella L, Letelier P, Brebi P. Brown Seaweed Fucoidan in Cancer: Implications in Metastasis and Drug Resistance. Marine Drugs. 2020; 18(5):232.

Chicago/Turabian Style

Reyes, María Elena, Ismael Riquelme, Tomás Salvo, Louise Zanella, Pablo Letelier, and Priscilla Brebi. 2020. "Brown Seaweed Fucoidan in Cancer: Implications in Metastasis and Drug Resistance" Marine Drugs 18, no. 5: 232.

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