In the United States, colon cancer ranks as the second most common cause of cancer-related deaths. Early-stage colon cancer can be successfully treated with surgery, but advanced-stage colon cancer frequently recurs and is fatal, even in patients receiving combination chemotherapy. Chemotherapeutic agents, including cisplatin, are routinely used to treat advanced-stage colon cancer, but the improvement in survival rates is minimal as a result of several factors, including drug resistance, side effects, and toxicity. Hence, fucoidan, a sulfate-containing polysaccharide that has no negative side effects, has been capturing people’s attention. Previous studies have shown that fucoidan has various biological activities, including anti-cancer, anti-inflammatory, anti-angiogenic, anticoagulant, and anti-human immunodeficiency virus activities.

However, the detailed inhibitory mechanism of fucoidan against colon cancer growth and metastasis has not yet been elucidated. So then, I would like to share the following study with you by YONG-SEOK HAN et al., “Fucoidan inhibits the migration and proliferation of HT-29 human colon cancer cells via the phosphoinositide-3 kinase/Akt/mechanistic target of rapamycin pathways”.

First, the effects of various fucoidan extracted from Fucus vesiculous concentrations (50, 100, and 200 μg/ml) on the proliferation of HT-29 cells were measured by measuring the viable cell count with an MTT assay. The number of viable HT-29 cells was reduced by Fucoidan in a manner that depended on the dose and time, as seen in Figure. 1A. In addition, they evaluated whether fucoidan affected the expression levels of cell cycle regulatory proteins, cyclin D1, cyclin E, CDK2, and CDK4. The maximum reduction of these proteins was observed after subjecting them to a 48-hour treatment with 200 μg/ml fucoidan, as clearly depicted in Figure 1B and C. These data demonstrated that fucoidan could inhibit the proliferation of colon cancer cells.

Extracellular matrix (ECM) degradation is also crucial for cell migration and invasion, indicating the inevitable involvement of matrix-degrading proteases. Thus, the impact of fucoidan on the expression of MMP-2, a crucial molecule implicated in ECM degradation, was assessed via Western blotting. MMP-2 expression gradually decreased with increasing fucoidan concentration. Since cell migration serves as an indicator of cancer cell metastatic potential, an investigation was conducted to examine the impact of fucoidan on cell migration through a wound-healing assay. HT-29 cells treated with fucoidan showed a decrease in cell migration. The results from the study indicate that fucoidan has the potential to suppress the migration properties of human colon cancer cells.

Additionally, these results demonstrated that fucoidan significantly inhibits the proliferation and migration of HT-29 cells and reduces the expression of MMP-2 in HT-29 cells. The specific signaling mechanism by which fucoidan affects cell proliferation and migration is still unknown. PI3K/Akt has been suggested to be a key pathway involved in the regulation of proliferation and migration. Figure 2A and B reveal that fucoidan significantly inhibited the phosphorylation of PI3K and its downstream target Akt in a dose- and time-dependent manner. The proliferation and migration of human colon cancer cells were effectively suppressed by fucoidan, potentially through the inhibition of the PI3K/Akt pathway.

Based on the finding that fucoidan suppresses the PI3K-Akt pathway in human HT-29 colon cancer cells, they investigated whether fucoidan regulates mTOR and its downstream signaling molecules. As shown in Figures 3A and B, fucoidan inhibited the phosphorylation of mTOR in a dose- and time-dependent manner. The phosphorylation of p70S6K, a direct downstream target of mTOR and an indicator of mTOR activity, was also significantly suppressed, as seen in Figures 3C and D.

Caspases are central effectors of apoptosis. To investigate the mechanism of fucoidan-induced apoptosis, the researchers used western blotting to detect anti-cleaved caspase-3. The administration of Fucoidan resulted in a gradual and proportional increase in the levels of cleaved caspase-3.

To generate spheroid cells, HT-29 cells were enzymatically dissociated and seeded on ultra-low attachment culture plates in a serum-free medium. After 3–5 days of culture, HT-29 cells were mostly viable and generated floating spherical colonies. To examine the formation ability of cancer spheroid cells, HT-29 cells were treated with fucoidan during spheroid cell formation. According to the results, fucoidan was found to inhibit the time-dependent formation of spheroid cells by HT-29 cells. In addition, 200 μg/ml of fucoidan reduced the efficiency of cancer spheroid cell formation.

The results of the experiment revealed that fucoidan had a significant impact on human HT-29 colon cancer cells. It effectively inhibited cell growth, migration, and rounding by suppressing the PI3K-Akt-mTOR pathway and decreasing MMP-2 expression. In the realm of cancer treatment, fucoidan is emerging as a promising therapeutic option, demonstrating the ability to inhibit the growth of human colon cancer cells.

Source: Mol Med Rep. 2015 Sep; 12(3): 3446–3452. doi: 10.3892/mmr.2015.3804