Oligo-Fucoidan extracted from Laminaria japonica is a sulfated polysaccharide with various biological and beneficial influences, such as anti-inflammatory and antitumor effects, and has also been shown to have beneficial health impacts.
The molecular mechanisms underlying the therapeutic effects of oligo-fucoidans in cancer patients remain unclear. Therefore, in this blog, I would like to share the study, “Oligo-Fucoidan prevents IL-6 and CCL2 production and cooperates with p53 to suppress ATM signaling and tumor progression” by Li-Mei Chen et al. In this study, researchers found that low-molecular-weight Fucoidan (oligo-fucoidan) treatment reduces the occurrence of spontaneous DNA lesions using human colorectal cancer HCT116 cells.
First, they have established that fucoidan subtly enhances DNA damage checkpoint activity improves therapeutic outcomes and mitigates the adverse effects of etoposide (chemo drug) on colorectal cancer cells. (p53−/−) or two isogenic HCT116 colorectal cancer cell lines with normal p53 expression (p53+/+) were used to compare the effect of monotherapy with that of concurrent or sequential combination therapy. Treatment of p53-/- and p53+/+ cells with different concentrations of oligo-fucoidan for 48 hours resulted in a significant dose-dependent decrease in p53+/+ cells. Oligo-fucoidan also suppressed p53 (Ser15) phosphorylation and p21 expression. (See Fig. 1a ) These effects imply oligo-fucoidans protect cells from intrinsic DNA damage.
Additionally, cells treated with etoposide (40 μM) for 6 hours and followed by treatment with oligo-fucoidan (200 μg/ml) at different intervals (0–3 days) were evaluated. Compared to p53+/+ cells treated with etoposide alone, γ-H2AX levels in p53+/+ cells after etoposide treatment were significantly enhanced by oligofucoidan supplementation. (See Fig. 2a b) Thus, these findings indicate that oligo-fucoidan supplementation protects cells from etoposide-associated genotoxicity, especially in the presence of p53.
Oligo-fucoidan also cooperates with p53 to reduce the action of the ATM signaling pathway, significantly suppressing tumor growth. Evaluating the activity of the ATM signaling pathway in different p53 backgrounds (See Fig. 2d), oligo-fucoidan (400 μg/ml) supplementation significantly inhibited the phosphorylation of ATM (Ser1981) and Chk1 (Ser317). Also, they observed that the phosphorylation of Chk2 (Thr68) was slightly reduced. In addition, the phosphorylation levels of ATM, Chk1, and H2AX were all significantly decreased in p53+/+ cells compared to co-treated p53-/- cells. The result showed that the ATM signaling cascade was co-inhibited by oligo-fucoidans and p53.
Later, to investigate the effect of oligo-fucoidan on IL-6 and CCL2 secretion from cancer cells, HCT116 cells (colorectal cancer) were treated with etoposide and oligo-fucoidan (400 μg/ml) or etoposide alone for 24 h. Then the cells were incubated cells in serum-free media for another 48 h. (See Fig. 3a) Analysis of IL-6 and CCL2 concentrations in conditioned media by quantitative ELISA showed that oligofucoidan prevented the etoposide-induced release of IL-6 and CCL2 from p53+/+ and p53−/− cells. As a result, it was confirmed that Etoposide-stimulated IL-6 and CCL2 secretion from HCT116 cancer cells were also specifically prevented by oligo-fucoidan in the presence of p53.
Furthermore, oligo-fucoidan treatment significantly reduced the M2 population of p53+/+ tumors, especially p53-/-. Tumors revealed that oligo-fucoidan could alter TME (tumor microenvironment) development independently of p53 status.
Significantly, oligo-fucoidan inhibits etoposide’s effects on promoting IL-6 and CCL2 signaling functions and reduces the M2 macrophage recruitment in TME. The IL-6/CCL2/EMT axis stimulates tumor progression and metastasis, suggesting that oligo-fucoidan supplementation may prevent tumor metastasis and recurrence. HCT116 cancer cells were also precisely controlled by oligo-fucoidan in the presence of p53.
These results indicate that oligo-fucoidan is a promising supplement for cancer treatment.
Source: Sci Rep. 2017; 7: 11864. doi: 10.1038/s41598-017-12111-1