Fucoidan
Therapies from Fucoidan: An Update
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584361/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584361/
There has been continuing interest in the use of fucoidan as an anti-cancer agent. An excellent review which can be used for general reference was presented by Kwak in 2014.
Kwak covers the main mechanisms by which fucoidan could act to inhibit cancer: scavenger receptor modulation; immune activation; anti-angiogenesis; the blockade of metastasis; mobilisation of stem cells and interference with SDF1/CXCR4 axis; anti-oxidant and pro-oxidant effects. As Kwak notes, the anti-cancer activity of fucoidan is likely to be via more than one single pathway [4].
The direct effects fucoidan on cancer cells are often via a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, mediated by PI3K/Akt and ERK signaling pathways [56]. More recent research indicates that fucoidan may induce apoptosis in breast and colon cancer cells via modulation of the endoplasmic reticulum stress cascades [57]. Co-cultured cell experiments, and then whole-animal experiments have also illustrated “anti-cancer” activities of fucoidan preparations from the standpoint of immune clearance of cancer cells, as described in the review by Kwak [4].
It may be the case that fucoidan exerts its effects via the gut, either by modulating immune cells directly, or secondarily, by altering the balance of microbiota.
More easily accessible cancers—such as those occurring within the gastrointestinal tract—could be exposed to orally delivered fucoidan without the need to consider uptake. Fucoidan may have utility as a sole agent, or adjunct agent, to delay or prevent the initiation of cancer. Other natural products have been assessed in colon cancer models, and this preventative approach can provide a route to developing a “functional food” for healthy colon [58].
One possible application is the use of fucoidan as an agent to reduce side-effects such as gastrointestinal mucosits during chemotherapy. A preparation of fucoidan (50–500 kDa), derived from the sea cucumber Acaudina molpadioides, was applied in a model of cyclophosphamide-induced intestinal mucositis in mice [59]. Cytokine levels were moderated, and the preparation was highly effective in restoring mucosal IgA. The common chemotherapy drug Cisplatin causes delayed motility, decreases in body weight and changes in the levels of gastric hormones gastrin and serotonin. Low molecular weight fucoidan prevented these changes in a manner similar to the commonly used drug, Ondansetron, suggesting that fucoidan can assist in maintaining normal gastrointestinal function during chemotherapy [60]. The effects in these chemotherapy-induced models is echoed in recent work showing that oral fucoidan (Fucus vesiculosus) was effective in reducing inflammation in a colitis model [61].
Secondly, fucoidan could be useful as an adjunct oral therapy during or after conventional chemotherapy or radiotherapy. Several studies, using in vitro models, have noted potential synergies with chemotherapy, as outlined in Table 3. However, as noted in cancer cell lines expressing EGFR receptors, the effects could also be antagonistic [62]. Zhang et al., using Cladosiphon fucoidan fractions, showed synergistic effects with three chemotherapy agents in two breast cancer cell lines [63]. In yet another type of cancer, human malignant lymphoid cell lines were pretreated with fucoidan prior to treatment with the chemotherapy drug etoposide, greatly increasing its efficacy [64].
Potential synergies with chemotherapy in in vitro and in vivomodels.
These early results are interesting, but require further cancer-specific, fraction-specific investigation, as well as translation into in vivo models.
Clinical studies in Japan have noted that ingestion of 4.05 g per day of fucoidan (Cladosiphon okamuranus) reduced the clinical toxicity indicator “fatigue” in a small cohort of subjects (10) undergoing oxaliplatin plus 5-fluorouracil/leucovorin or irinotecan plus 5-fluo-rouracil/leucovorin chemotherapy for unresectable colon cancer, compared to those not taking fucoidan [65]. Patients taking fucoidan were able to tolerate more rounds of chemotherapy. At this stage it is unclear why this might be the case, but the observations warrant follow-up studies. Fatigue during exercise was investigated in a mouse model, and found to be reduced by oral Laminaria japonica fucoidan at an equivalent human dose of 1.5 g per day [66]. In the model, the reduced fatigue was associated with decreased serum lactate and ammonia, increased serum glucose and lower serum triglyceride levels.
In a recent Australian interaction study, the effects of fucoidan on the drug levels in the serum of subjects with breast cancer were monitored, for patients taking the common hormone drugs tamoxifen or letrozole. There was no significant interaction with these long term treatments, showing that fucoidan at 1 g per day was safe [67]. Any proposed use for fucoidan as an adjunct to chemotherapy should ensure that it does not interfere with serum pharmacokinetics of the chemotherapy drugs. This provides reassurance to patients and physicians.
Amongst the many variations in fucoidans, and variations in cancer types, there appear to be broad patterns for mechanisms of anti-cancer activity. Not all cancers will respond in the same way at the direct cellular level, yet cancer inhibitory effects may be mediated in vivo via immune stimulation or anti-metastatic mechanisms.
Fucoidan is known to interfere with the binding of a cellular receptor called “CXCR4” to a chemokine known as “CXCL12” or “stromal derived factor 1”, chiefly by binding to CXCL12 [68,69]. The binding of these receptors can be critical for the establishment, growth and metastasis of tumors, so prevention of binding may assist in inhibiting cancer. Since Kwak’s review which also discussed this subject, fucoidan from Saccharina latissimi and Fucus vesiculosus and heparin were investigated for their effects on human Burkitt’s lymphoma cells [70]. The fucoidan fractions bound CXCL12, and thus prevented CXCR4 binding and the downstream effects such as secretion of matrix-degrading enzymes necessary for metastasis. In this case, the higher molecular weight, unfractioned fucoidan was more effective than the smaller sub-fractions, once again illustrating subtle differences in biological activity. Fucoidan may lessen the effects of acute pancreatitis (inflammation rather than cancer), possibly as a result of the ability of fucoidan to block selectins [71]. The effects of fucoidan from the lesser known brown algae, Turbinaria conoides, have been studied in vitro using a specific pancreatic cancer cell line. The research indicated that fucoidan decreased the ability of cancer cells to secrete the matrix-degrading enzymes they required to metastasize and spread [72]. Interestingly, pancreatic cancer is also highly dependent on CXCR4 to spread. Recent research showed that the CXCR4 inhibitor plerixafor was effective in blocking the metastatic potential of pancreatic cancer in a mouse model [73], indicating once more a potential role for fucoidan fractions to be investigated in this application.
In a Lewis lung cancer model in mice, oral Fucus vesiculosus fucoidan lessened body weight loss and reduced lung masses [74]. Unusually, the fucoidan was pretreated with simulated gastric and intestinal juices prior to administration. In this comprehensive study, fucoidan down-regulated the expression of a number of key markers associated with tumor development, spread and proliferation. These markers included matrix metalloproteinases, NF-κB and vascular endothelial growth factor (VEGF). The focus on VEGF reflects a current interest in drugs that block the spread of cancers expressing this marker, such as the antibody drug bevacizumab, used extensively in advanced cancers to block angiogenesis [75]. In this study, fucoidan showed promise as chemo-preventative agent for minimizing weight loss symptoms and reducing tumor proliferation. The ability of fucoidan to reduce expression of VEGF is also displayed in recent research into macular degeneration [76]. Fucoidan reduced VEGF expression in retinal pigment epithelial cells, and the effects were additive to bevacizumab, showing that fucoidan could be considered as an adjunct agent.
Survival rates are low for many types of liver cancer—including poorly differentiated hepatocellular carcinoma. Recent research investigated the effects of fucoidan on cells from this cancer type in vitro. The researchers studied the effects of fucoidan on a proliferation regulator known as AMP-activated protein kinase (AMPK), as well as its downstream metabolism and cell cycle-related molecules, in a poorly differentiated human hepatoma HLF cell line. The results suggested that fucoidan inhibited proliferation of the cancer cells via the AMPK-associated suppression of fatty acid synthesis and cell cycle G1/S transition [77]. This data is reflected by several other papers describing effects of fucoidan on normal and carcinoma-like hepatocellular lines including HepG2 [78].
Oral cancers present treatment challenges, and may be accessible to localised application of fucoidan. Fucoidan causes apoptosis in a particular type of oral cancer called “mucoepidermoid carcinoma” [79]. Fucoidan decreased cell proliferation and induced caspase-dependent apoptosis via down-regulation of phosphorylation of the extracellular signal-regulated kinase ERK1/2. Fucoidan holds promise as a therapeutic agent for treatment of this type of oral cancer and should be investigated further.
Lastly, prostate cancer is a globally significant disease and one of the most common causes of cancer death in men. In a new Korean study, the anti-cancer effect of fucoidan from Undaria pinnatifidawas assessed in vitro using human prostate cancer cells (PC-3). Fucoidan was shown to induce apoptosis of cancerous PC-3 cells in a manner that suggested fucoidan could induce both “intrinsic” and “extrinsic” apoptosis pathways. The results of this study offer encouraging prospects for the potential of fucoidan in the treatment of prostate cancer if bioavailability and delivery can be addressed successfully.
Kwak covers the main mechanisms by which fucoidan could act to inhibit cancer: scavenger receptor modulation; immune activation; anti-angiogenesis; the blockade of metastasis; mobilisation of stem cells and interference with SDF1/CXCR4 axis; anti-oxidant and pro-oxidant effects. As Kwak notes, the anti-cancer activity of fucoidan is likely to be via more than one single pathway [4].
The direct effects fucoidan on cancer cells are often via a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, mediated by PI3K/Akt and ERK signaling pathways [56]. More recent research indicates that fucoidan may induce apoptosis in breast and colon cancer cells via modulation of the endoplasmic reticulum stress cascades [57]. Co-cultured cell experiments, and then whole-animal experiments have also illustrated “anti-cancer” activities of fucoidan preparations from the standpoint of immune clearance of cancer cells, as described in the review by Kwak [4].
It may be the case that fucoidan exerts its effects via the gut, either by modulating immune cells directly, or secondarily, by altering the balance of microbiota.
More easily accessible cancers—such as those occurring within the gastrointestinal tract—could be exposed to orally delivered fucoidan without the need to consider uptake. Fucoidan may have utility as a sole agent, or adjunct agent, to delay or prevent the initiation of cancer. Other natural products have been assessed in colon cancer models, and this preventative approach can provide a route to developing a “functional food” for healthy colon [58].
One possible application is the use of fucoidan as an agent to reduce side-effects such as gastrointestinal mucosits during chemotherapy. A preparation of fucoidan (50–500 kDa), derived from the sea cucumber Acaudina molpadioides, was applied in a model of cyclophosphamide-induced intestinal mucositis in mice [59]. Cytokine levels were moderated, and the preparation was highly effective in restoring mucosal IgA. The common chemotherapy drug Cisplatin causes delayed motility, decreases in body weight and changes in the levels of gastric hormones gastrin and serotonin. Low molecular weight fucoidan prevented these changes in a manner similar to the commonly used drug, Ondansetron, suggesting that fucoidan can assist in maintaining normal gastrointestinal function during chemotherapy [60]. The effects in these chemotherapy-induced models is echoed in recent work showing that oral fucoidan (Fucus vesiculosus) was effective in reducing inflammation in a colitis model [61].
Secondly, fucoidan could be useful as an adjunct oral therapy during or after conventional chemotherapy or radiotherapy. Several studies, using in vitro models, have noted potential synergies with chemotherapy, as outlined in Table 3. However, as noted in cancer cell lines expressing EGFR receptors, the effects could also be antagonistic [62]. Zhang et al., using Cladosiphon fucoidan fractions, showed synergistic effects with three chemotherapy agents in two breast cancer cell lines [63]. In yet another type of cancer, human malignant lymphoid cell lines were pretreated with fucoidan prior to treatment with the chemotherapy drug etoposide, greatly increasing its efficacy [64].
Potential synergies with chemotherapy in in vitro and in vivomodels.
These early results are interesting, but require further cancer-specific, fraction-specific investigation, as well as translation into in vivo models.
Clinical studies in Japan have noted that ingestion of 4.05 g per day of fucoidan (Cladosiphon okamuranus) reduced the clinical toxicity indicator “fatigue” in a small cohort of subjects (10) undergoing oxaliplatin plus 5-fluorouracil/leucovorin or irinotecan plus 5-fluo-rouracil/leucovorin chemotherapy for unresectable colon cancer, compared to those not taking fucoidan [65]. Patients taking fucoidan were able to tolerate more rounds of chemotherapy. At this stage it is unclear why this might be the case, but the observations warrant follow-up studies. Fatigue during exercise was investigated in a mouse model, and found to be reduced by oral Laminaria japonica fucoidan at an equivalent human dose of 1.5 g per day [66]. In the model, the reduced fatigue was associated with decreased serum lactate and ammonia, increased serum glucose and lower serum triglyceride levels.
In a recent Australian interaction study, the effects of fucoidan on the drug levels in the serum of subjects with breast cancer were monitored, for patients taking the common hormone drugs tamoxifen or letrozole. There was no significant interaction with these long term treatments, showing that fucoidan at 1 g per day was safe [67]. Any proposed use for fucoidan as an adjunct to chemotherapy should ensure that it does not interfere with serum pharmacokinetics of the chemotherapy drugs. This provides reassurance to patients and physicians.
Amongst the many variations in fucoidans, and variations in cancer types, there appear to be broad patterns for mechanisms of anti-cancer activity. Not all cancers will respond in the same way at the direct cellular level, yet cancer inhibitory effects may be mediated in vivo via immune stimulation or anti-metastatic mechanisms.
Fucoidan is known to interfere with the binding of a cellular receptor called “CXCR4” to a chemokine known as “CXCL12” or “stromal derived factor 1”, chiefly by binding to CXCL12 [68,69]. The binding of these receptors can be critical for the establishment, growth and metastasis of tumors, so prevention of binding may assist in inhibiting cancer. Since Kwak’s review which also discussed this subject, fucoidan from Saccharina latissimi and Fucus vesiculosus and heparin were investigated for their effects on human Burkitt’s lymphoma cells [70]. The fucoidan fractions bound CXCL12, and thus prevented CXCR4 binding and the downstream effects such as secretion of matrix-degrading enzymes necessary for metastasis. In this case, the higher molecular weight, unfractioned fucoidan was more effective than the smaller sub-fractions, once again illustrating subtle differences in biological activity. Fucoidan may lessen the effects of acute pancreatitis (inflammation rather than cancer), possibly as a result of the ability of fucoidan to block selectins [71]. The effects of fucoidan from the lesser known brown algae, Turbinaria conoides, have been studied in vitro using a specific pancreatic cancer cell line. The research indicated that fucoidan decreased the ability of cancer cells to secrete the matrix-degrading enzymes they required to metastasize and spread [72]. Interestingly, pancreatic cancer is also highly dependent on CXCR4 to spread. Recent research showed that the CXCR4 inhibitor plerixafor was effective in blocking the metastatic potential of pancreatic cancer in a mouse model [73], indicating once more a potential role for fucoidan fractions to be investigated in this application.
In a Lewis lung cancer model in mice, oral Fucus vesiculosus fucoidan lessened body weight loss and reduced lung masses [74]. Unusually, the fucoidan was pretreated with simulated gastric and intestinal juices prior to administration. In this comprehensive study, fucoidan down-regulated the expression of a number of key markers associated with tumor development, spread and proliferation. These markers included matrix metalloproteinases, NF-κB and vascular endothelial growth factor (VEGF). The focus on VEGF reflects a current interest in drugs that block the spread of cancers expressing this marker, such as the antibody drug bevacizumab, used extensively in advanced cancers to block angiogenesis [75]. In this study, fucoidan showed promise as chemo-preventative agent for minimizing weight loss symptoms and reducing tumor proliferation. The ability of fucoidan to reduce expression of VEGF is also displayed in recent research into macular degeneration [76]. Fucoidan reduced VEGF expression in retinal pigment epithelial cells, and the effects were additive to bevacizumab, showing that fucoidan could be considered as an adjunct agent.
Survival rates are low for many types of liver cancer—including poorly differentiated hepatocellular carcinoma. Recent research investigated the effects of fucoidan on cells from this cancer type in vitro. The researchers studied the effects of fucoidan on a proliferation regulator known as AMP-activated protein kinase (AMPK), as well as its downstream metabolism and cell cycle-related molecules, in a poorly differentiated human hepatoma HLF cell line. The results suggested that fucoidan inhibited proliferation of the cancer cells via the AMPK-associated suppression of fatty acid synthesis and cell cycle G1/S transition [77]. This data is reflected by several other papers describing effects of fucoidan on normal and carcinoma-like hepatocellular lines including HepG2 [78].
Oral cancers present treatment challenges, and may be accessible to localised application of fucoidan. Fucoidan causes apoptosis in a particular type of oral cancer called “mucoepidermoid carcinoma” [79]. Fucoidan decreased cell proliferation and induced caspase-dependent apoptosis via down-regulation of phosphorylation of the extracellular signal-regulated kinase ERK1/2. Fucoidan holds promise as a therapeutic agent for treatment of this type of oral cancer and should be investigated further.
Lastly, prostate cancer is a globally significant disease and one of the most common causes of cancer death in men. In a new Korean study, the anti-cancer effect of fucoidan from Undaria pinnatifidawas assessed in vitro using human prostate cancer cells (PC-3). Fucoidan was shown to induce apoptosis of cancerous PC-3 cells in a manner that suggested fucoidan could induce both “intrinsic” and “extrinsic” apoptosis pathways. The results of this study offer encouraging prospects for the potential of fucoidan in the treatment of prostate cancer if bioavailability and delivery can be addressed successfully.
CLICK ON THE "R" BELOW FOR RESEARCH DETAILS
Fucoidan fights cancer by immune cell activation and increased production of anticancer cytokines [R, R, R].
Fucoidan extracted from bladderwrack cause cell death in various human cancer cells, including leukemia, breast cancer, stomach cancer, lung cancer, prostate cancer, and liver cancer cells [R, R, R, R, R, R, R].
Fucoidan blocked cell growth, caused programmed cell death, and suppressed formation of new blood cells in thyroid cancer cells [R].
The disease control rate (DCR) is the percentage of patients who have achieved complete response, partial response, and stable disease from a therapy. In a study (DB-RCT) of 54 patients with colorectal cancer, 4,000 mg fucoidan powder in addition to chemotherapy resulted in a DCR of 92%, compared to 69% in the placebo group [R].
Fucoidan fights cancer by immune cell activation and increased production of anticancer cytokines [R, R, R].
Fucoidan extracted from bladderwrack cause cell death in various human cancer cells, including leukemia, breast cancer, stomach cancer, lung cancer, prostate cancer, and liver cancer cells [R, R, R, R, R, R, R].
Fucoidan blocked cell growth, caused programmed cell death, and suppressed formation of new blood cells in thyroid cancer cells [R].
The disease control rate (DCR) is the percentage of patients who have achieved complete response, partial response, and stable disease from a therapy. In a study (DB-RCT) of 54 patients with colorectal cancer, 4,000 mg fucoidan powder in addition to chemotherapy resulted in a DCR of 92%, compared to 69% in the placebo group [R].
Fucoidan and Cancer: A Multifunctional Molecule with Anti-Tumor Potential
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413214
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413214
Fucoidan inhibits the migration and proliferation of HT-29 human colon cancer cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526071/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526071/
Fucoidan present in brown algae induces apoptosis of human colon cancer cells.
https://www.ncbi.nlm.nih.gov/pubmed/20727207
https://www.ncbi.nlm.nih.gov/pubmed/20727207