Fucoidan, which is a naturally-occurring compound, has been found in various species of brown algae and is currently attracting attention due to its anti-cancer properties. In order to understand Fucoidan’s anti-cancer mechanisms, it’s important to consider the pathways it affects, as well as its structure and bioavailability. Hence, in this blog, I would like to introduce the research, “Fucoidan Structure and Activity in Relation to Anti-Cancer Mechanisms” by Geert van Weelden et al. The benefits of Fucoidan are explored in depth in this study and the findings are presented.

First, the main pathways affected by Fucoidan are PI3K/AKT, MAPK pathway, and caspase pathway. Researchers believe that PTEN, which plays a crucial role in the development of many cancers, is vital in the AKT pathway affected by Fucoidan. In addition to its numerous other applications, Fucoidan also has the ability to serve as an adjuvant, which can improve the efficacy of chemotherapy and reduce the harmful effects on healthy cells.

According to animal model studies, the repeated administration of Fucoidan at relatively high doses did not result in any toxic reactions. This is consistent with in vitro results of Fucoidan on healthy human cells from other studies.

First, the PI3K/AKT pathway (the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B signaling pathway) is central to a variety of cellular functions. The pathway that is frequently upregulated in tumor cells is often a target for cancer therapy due to its frequent activation. The ability of tumor cells to resist cell death and migrate is associated with the upregulation of the PI3K/AKT pathway. Studies have found that the PI3K/AKT pathway is involved in stimulating the expression of various matrix metalloproteinases (MMPs) in cancer cells. The MMPs, also known as matrix metalloproteinases, play a significant role in the breakdown of the extracellular matrix (ECM) and are frequently expressed in metastatic cancer cells.

Some example, Fucoidan (U. pinnatifida) inhibited the phosphorylation of PI3K/AKT in prostate cancer cell lines in vitro. AML( Acute myeloid leukemia) cell lines showed a decrease in phosphorylated AKT in vitro when treated with Fucoidan. A Fucoidan extract from F. The in vitro testing of vesiculosus was conducted on a range of female cancer cell lines, including breast, ovarian, uterine, and endometrial. Fucoidan treatment decreased phosphorylated PI3K, AKT, and mTOR in most cancer cell lines. Decreased activity of mTOR triggered autophagy in the tested cell lines.

However, some cancer cells appear to have little sensitivity to the effects of certain Fucoidans. It is a well-known fact that mutations in G protein-coupled receptors are present in all cell lines, leading to the activation of GTP state and the initiation of intracellular signaling pathways responsible for cell proliferation. This causes hyperactivation of the MAPK, PKC, and PI3K/AKT pathways. The inhibitory effect of Fucoidan is considered insufficient to have a significant effect on the proliferation of some cancer cells.

Therefore, although Fucoidan can interact with the PI3K/AKT pathway to reduce both cell proliferation and migration, not all cancer types are affected.

The MAPK/ERK pathway has multiple components and is often mutated into various cancer types.  (See Figure 1). The MAPK/ERK pathway is also involved in cell migration and invasion. The p38 MAPK and JNK pathways are also involved in tumorigenesis. Although several studies have reported the regulation of p38 MAPK by Fucoidan, their relationship is still not entirely clear. Here, researchers describe the ERK1/2 and p38 MAPK pathways.

In human lymphoma cell lines, Fucoidan (F. vesiculosus) reduces protein levels of phosphorylated ERK1/2 in vitro, which may be important for the induction of apoptosis. Similar to the PI3K/AKT pathway, ERK1/2 can improve cells from undergoing apoptosis. In breast cancer cell lines, Fucoidan (F. vesiculosus) induced apoptosis and in vitro, it reduced ERK1/2, survivin, and Bcl-2 protein levels. In vitro studies showed that healthy mouse fibroblasts were not affected by Fucoidan.

In order to clarify the cellular mechanism of Fucoidan-mediated ERK1/2 inhibition, an evaluation was conducted on all known mutations and receptor expressions in various cancer cell types. However, for some cancer cell lines, we found possible explanatory clues in the existing literature. For example, U937 leukemia cells constitutively have lower MAPK activity and have proven to be more resistant to MAPK-targeted therapy.

The caspase pathway plays a central role in both intrinsic and extrinsic induction of apoptosis. When caspases are activated by cleavage, they activate apoptotic pathways. In an in vitro study on a human mucoepidermoid carcinoma cell line, Fucoidan (F. vesiculosus) induced apoptosis by activating caspase-3. In mouse breast cancer, Fucoidan (F. vesiculosus) induced her Cyt c release in vivo and in vitro. Fucoidan-induced apoptosis in human breast cancer cells by caspase-3 cleavage. It was observed that the same effect was present in mice, as seen in vivo. Fucoidan can activate the caspase pathway, proving the pluripotency of Fucoidan.

In conclusion, based on the results obtained in preclinical studies, Fucoidan has anti-tumor properties and is considered promising in cancer treatment.

Source: Mar Drugs. 2019 Jan; 17(1): 32. doi: 10.3390/md17010032