Fucoidan, which is derived from brown algae, is a type of sulfated polysaccharide. Their ability to target various signaling pathways and molecular mechanisms within malignant cells gives them anticancer properties. In this blog, I would like to share the study, “Brown Seaweed Fucoidan in Cancer: Implications in Metastasis and Drug Resistance” by María Elena Reyes et al. The major hurdles in cancer treatment, namely metastasis and drug resistance, are the focal points of the discussion in this blog. It is important to note that fucoidan has been the subject of clinical trials, aiming to evaluate its potential synergistic impact when combined with other anticancer therapies, as indicated in the study.

The emergence of chemotherapy resistance poses a major obstacle in the field of cancer treatment. This resistance is described as the ability of cancer cells to evade the effects of chemotherapy, whether through natural means or through acquisition. For example, repeated chemotherapeutic stimulation induces pro-survival biological changes in tumor cells that allow them to use host or tumor-associated factors to circumvent cell death under drug pressure. The induction of cellular stress in “susceptible cells” by various chemotherapeutic agents such as platinum agents and taxanes is a common mechanism in cancer treatment, ultimately resulting in cell death. This process is primarily mediated by apoptotic pathways.

There are four primary mechanisms contributing to drug resistance in cancer cells: (1) Reduced uptake of water-soluble drugs; (2) Alterations in intracellular pathways that affect the potential of cytotoxic drugs to kill cells, including cell cycle changes, DNA repair, apoptotic pathways, drug metabolism/elimination, etc. (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), and (4) Intracellular detoxifiers such as antioxidants (such as glutathione). There are various signaling pathways that have been associated with chemotherapy resistance, and it is crucial to develop innovative therapeutic strategies to address this issue.

Certain Fucoidans have been linked to the reduction of drug resistance in cancer treatment. For example, fucoidan derived from A. nodosum has been shown to arrest the G1 phase of the cell cycle and reduce chemotherapy resistance to cisplatin in non-small cell human bronchial lung cancer (NSCLC-N6) cells, a type of chemotherapy-resistant cell line. The same study also showed the antitumor effects of fucoidan at sub-toxic doses in vivo in NSCLC-bearing nude mice. Fucoidan obtained from F. veciculosus was able to reduce the expression of cellular prion protein (PrPC) in the HT29 colon cancer cell line. The protein PrPC plays a role in suppressing stress response proteins p38, JNK, and p53. Overexpression of PrPC can lead to enhanced cell survival, proliferation, and resistance to drugs.

Recently, it has been discovered that cytokines play a direct role in the advancement of cancer. They promote the growth and spread of cancer cells, alter the tumor microenvironment, help the cancer cells evade the immune system, and facilitate the development of new blood vessels within tumors. It is also often associated with chemoresistance and poor overall prognosis. In addition, fucoidan has the ability to suppress the production of specific cytokines and chemokines, which can inhibit the movement of tumor cells and the recruitment of lymphocytes through NF-κB-dependent transcription.

Fucoidan can also function as an adjuvant when used alongside chemotherapy. For example, it has been demonstrated that sulfated polysaccharides can increase the bioavailability of certain oral drugs such as doxorubicin. Fucoidan from U. pinnatifida and F. vesiculosus was studied in combination with tamoxifen and paclitaxel in orthotopic mouse models of breast and ovarian cancer. The results indicated that both fucoidans enhanced the effectiveness of tamoxifen in treating breast cancer, but not paclitaxel. It was shown that the effect did not improve. Only F. vesiculosus-derived fucoidan demonstrated the ability to enhance the effectiveness of tamoxifen in an ovarian cancer model, while paclitaxel showed no such improvement. The use of Fucoidan from Fucus vesiculosus has been proven to heighten the cytotoxicity of cisplatin against lung cancer cell lines. This is achieved by promoting the expression of cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP), leading to the induction of apoptosis in the cells. In addition, this fucoidan has the ability to work together with gefitinib to trigger apoptosis in lung cancer cells.

Fucoidan from U. pinnatifida is also being studied in melanoma, an inherently aggressive and treatment-resistant cancer that can develop resistance to the ERBB inhibitor lapatinib. When used alone, Lapatinib was able to inhibit 60% of tumor growth; however, when combined with fucoidan, tumor growth was reduced by 85%. The use of fucoidan can reduce the morbidity associated with long-term lapatinib treatment. The potential use of fucoidan extracts is further advantageous due to their ability to avoid side effects. Another fucoidan extracted from Cladosiphon navae-caledoniae Kylin can be combined with cisplatin, tamoxifen, or paclitaxel to improve breast cancer treatment outcomes. These simultaneous treatments significantly inhibited cell proliferation of MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, it enhanced apoptosis in these cells by downregulating anti-apoptotic proteins Bcl-xL and Mcl-1 and promoting increased intracellular ROS levels.

The utilization of fucoidan-based approaches has the potential to revolutionize the field of cancer treatment by addressing the inherent limitations of the most complex forms of the disease. These approaches can effectively combat metastasis and drug resistance, while simultaneously improving the response rate and overall quality of chemotherapy. Further investigation into fucoidan is necessary to enhance our understanding of how these compounds can effectively hinder metastasis and multidrug resistance in various forms of cancer, ultimately improving the lives of cancer patients.

Source: Mar. Drugs 2020, 18(5), 232; https://doi.org/10.3390/md18050232

​