In this blog, I would like to share the study, “Ten Years of Research on Fucoidan and Cancer: Focus on Its Antiangiogenic and Antimetastatic Effects” by Eleonora Turrini et al. The primary focus of this study was the anti-angiogenic and anti-metastatic effects of fucoidan, with a specific emphasis on ten years of preclinical research.
Angiogenesis, the process of blood vessel formation, is primarily induced by hypoxia. It can also be triggered by various stimuli including acidic pH, hypoglycemia, hypertension, mechanical stress, chronic inflammation, and oxidative stress, all of which have the potential to promote angiogenesis. Hypoxia-sensitive tissues release HIF-1α (hypoxia-inducible factor-1α). HIF-1α binds to hypoxia response elements and activates transcription of other proangiogenic factors. There is increasing evidence that the PI3K (phosphatidylinositol-3 kinase)/Akt (protein kinase B)/mTOR (mammalian target of rapamycin) pathway functions as a master switch controlling HIF-1α synthesis. The activation of erythropoietin, glucose transporters, glycolytic enzymes, VEGF, and gene transcription by HIF-1α results in increased oxygen supply or the development of hypoxic conditions, thus facilitating metabolic adaptation and angiogenesis.
Fucoidan has the ability to suppress the expression of VEGF and HIF-1α, which are crucial regulators of angiogenesis, in different cancer cell lines. It is worth noting that fucoidan not only downregulated VEGF, but its effects were enhanced when combined with paclitaxel and cisplatin, which are anticancer drugs. Treatment with fucoidan and chemotherapeutic agents resulted in a notable increase in the expression of KDR (kinase insert domain receptor) and FLT4 (FMS-related tyrosine kinase 4) genes in ovarian cancer cells, which are known to be associated with angiogenesis.
In terms of providing examples, the Fucoidan that was extracted from kelp and tested on triple-negative breast cancer cells (MDA-MB-231 and HCC1806 cells) showed significant effects. This was demonstrated through a transwell assay, which revealed a correlation between fucoidan and the downregulation of VEGFA and IGF-I. Additionally, the production of proangiogenic factors such as bFGF, MMP-2, and MMP-9 was suppressed, leading to a reduction in invasion and migration capabilities. Increased expression of DNMT3B in human hepatocellular carcinoma is inversely related to the expression of MTSS1, a metastasis suppressor protein. Targeting the miR-29b-DNMT3B-MTSS1 pathway could potentially enhance the treatment of hepatocellular carcinoma. Fucoidan, a compound, has been found to upregulate miR-29b, downregulate DNMT3B, promote the expression of MTSS1, inhibit epithelial-mesenchymal transition (EMT), and prevent extracellular matrix (ECM) degradation.
The concentration-dependent manner in which Sargassum fusiforme fucoidan (FP08S2) was able to block migration and invasion of HMEC-1 cells was observed, and this can be attributed to its ability to bind to both VEGF-VEGFR2. It is important to note that this binding did not affect the viability of HMEC-1 cells, thus preventing their interaction. Angiogenesis is inhibited through the prevention of the activation of the MAPK/PI3K signaling pathway, as well as VEGFR2 and its downstream targets ERK and mTOR.
The study examined how Sargassum-derived fucoidan FP08S2 affects the molecular pathways that control angiogenesis inhibition in human HMEC-1 microvascular endothelial cells. FP08S2 inhibited the migration and invasion of HMEC-1 cells in a concentration-dependent manner. The migratory and anti-invasive effects are attributed to the binding of both VEGF-VEGFR2 without compromising the viability of HMEC-1 cells, which means their interaction is not tolerated. This blocks activation of the MAPK/PI3K signaling pathway by VEGFR2 and its downstream targets ERK and mTOR, inhibiting angiogenesis.
Now, let’s take a look at some examples of the most significant clinical evidence from the past decade that have been compiled below.
A study involving 20 patients with advanced cancer aimed to assess the impact of fucoidan on patients’ quality of life and inflammation levels. The findings suggest that fucoidan may also enhance the effectiveness of chemotherapy. Patients with diverse primary tumor origins and distant metastases were enrolled in a single-arm clinical study. It is important to note that the majority (90%) of these patients had already undergone standard chemotherapy for advanced cancer before being treated with fucoidan. Each patient received 400 mL of fucoidan per day for 4 weeks. Pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor-α (TNF-α) were significantly reduced after 2 weeks of fucoidan intake. Importantly, a decrease in IL-8 levels was found to be significantly linked with improved overall survival in individuals with cancer.
One of the major obstacles faced in cancer treatment lies in the identification of successful approaches to mitigate the toxicity associated with radiotherapy and chemotherapy.
Cisplatin is a well-known chemotherapy drug used to treat many types of cancer. The administration of cisplatin often faces challenges due to the occurrence of severe side effects in cancer patients. A study was conducted to examine the effectiveness of fucoidan in minimizing the side effects of cisplatin treatment in 24 patients with advanced, inoperable gastric cancer. Patients were randomly assigned to a fucoidan treatment group (n = 12) or a control group without fucoidan treatment (n = 12). Cisplatin treatment was administered to all 24 participants. For a duration of 6 months, patients in the fucoidan group took in a liquid containing 4.05 g of high-molecular-weight fucoidan derived from Cladosiphon cumulants, with a daily intake of 150 mL. Fucoidan was found to decrease the incidence of diarrhea and alleviate fatigue in patients undergoing chemotherapy. Fucoidan maintained a good nutritional status in patients during chemotherapy and prevented the deterioration of the prognostic nutritional index caused by cisplatin.
The complex anti-angiogenic profile of fucoidan makes it a strong contender for utilization alongside traditional anti-cancer strategies, with the aim of impeding the development of cancer. It is worth emphasizing that the characteristics of fucoidan, including its source, structure, and other properties, have a significant impact on its overall efficacy, as highlighted in Figure 2.
Source: Mar Drugs. 2023 May; 21(5): 307. doi: 10.3390/md21050307