Oligo-Fucoidan Prevents M2 Macrophage Differentiation and HCT116 Tumor Progression

Abstract

Reactive oxygen species (ROS) produced during intracellular metabolism or triggered by extrinsic factors can promote neoplastic transformation and malignant microenvironment that mediate tumor development. Oligo-Fucoidan is a sulfated polysaccharide isolated from the brown seaweed. Using human THP-1 monocytes and murine Raw264.7 macrophages as well as human HCT116 colorectal cancer cells, primary C6P2-L1 colorectal cancer cells and human MDA-MB231 breast cancer cells, we investigated the effect of Oligo-Fucoidan on inhibiting M2 macrophage differentiation and its therapeutic potential as a supplement in chemotherapy and tumor prevention. We now demonstrate that Oligo-Fucoidan is an antioxidant that suppresses intracellular ROS and mitochondrial superoxide levels in monocytes/macrophages and in aggressive cancer cells. Comparable to ROS inhibitors (DPI and NAC), Oligo-Fucoidan directly induced monocyte polarization toward M1-like macrophages and repolarized M2 macrophages into M1 phenotypes. DPI and Oligo-Fucoidan also cooperatively prevented M2 macrophage invasiveness. Indirectly, M1 polarity was advanced particularly when DPI suppressed ROS generation and supplemented with Oligo-Fucoidan in the cancer cells. Moreover, cisplatin chemoagent polarized monocytes and M0 macrophages toward M2-like phenotypes and Oligo-Fucoidan supplementation reduced these side effects. Furthermore, Oligo-Fucoidan promoted cytotoxicity of cisplatin and antagonized cisplatin effect on cancer cells to prevent M2 macrophage differentiation. More importantly, Oligo-Fucoidan inhibited tumor progression and M2 macrophage infiltration in tumor microenvironment, thus increasing of anti-tumor immunity.

Present Status, Limitations and Future Directions of Treatment Strategies Using Fucoidan-Based Therapies in Bladder Cancer

“…Similarly, there was a report that extract from the seaweed Cladosiphon novae-caledoniae consisting of a digested small molecular weight fraction (72%; <500 Da) and a non-digested fraction (less than 28%; peak = 800 kDa) enhanced the anti-cancer effects of CDDP via inhibitory effects on cell growth (using 200 and 400 μg/mL fucoidan extract for 48 h) and the pro-apoptotic activity (using 200 μg/mL fucoidan extract for 24 and 48 h) in breast cancer cells (MDA-MB-231 and MCF-7 cells) [ 64 ]. Furthermore, in recent years, oligo-fucoidan (molecular weight: 92.1%; 500–800 Da) has been reported to promote the cytotoxic activity of CDDP in colon cancer cells [ 12 ]. Briefly, in primary C6P2-L1 cell lines derived from colorectal cancer patients, the number of apoptotic cells in the group treated with a combination of CDDP and oligo-fucoidan was significantly higher than those in groups treated with CDDP alone or oligo-fucoidan alone, and upregulation of PARP cleavage and caspase-3 activation were associated with these results [ 12 ].…”

“…Furthermore, in recent years, oligo-fucoidan (molecular weight: 92.1%; 500–800 Da) has been reported to promote the cytotoxic activity of CDDP in colon cancer cells [ 12 ]. Briefly, in primary C6P2-L1 cell lines derived from colorectal cancer patients, the number of apoptotic cells in the group treated with a combination of CDDP and oligo-fucoidan was significantly higher than those in groups treated with CDDP alone or oligo-fucoidan alone, and upregulation of PARP cleavage and caspase-3 activation were associated with these results [ 12 ]. This study also showed that oligo-fucoidan enhanced the anti-tumor effects of CDDP in colorectal cancer cells in vivo.…”

“…This study also showed that oligo-fucoidan enhanced the anti-tumor effects of CDDP in colorectal cancer cells in vivo. Briefly, in a xenograft model with subcutaneous injection of HCT 116 cells, tumor volume in the group with a combination treatment of CDDP and oligo-fucoidan was significantly lower than that in the group with CDDP treatment alone [ 12 ]. Notably, such additional anti-tumor growth effects of fucoidan with CDDP were detected in p53 +/+ tumors only and not in p53 −/− tumors [ 12 ].…”

“…In recent years, immune therapies have been used as standard treatment methods in various types of malignancies, including BC, and many investigators have paid special attention to the development and modification of this therapy [ 105 , 106 , 107 ]. Fucoidans play significant roles in mutation of dendritic cells, activity of T and B lymphocytes, macrophages, and natural killer cells, and differentiation of macrophages in different experimental models, including cancer xenograft models [ 12 , 99 , 108 , 109 , 110 ]. Importantly, such an immune system is closely associated with malignant potential and outcome of BC cells [ 111 , 112 , 113 , 114 ].…”

“…Additionally, fucoidan has been favored owing to its low toxicity in vivo, including in humans [ 9 , 10 ]. Furthermore, there is a general agreement that fucoidan exerts anti-cancer effects by regulating tumor growth, cancer cell apoptosis, invasion, metastasis, cell cycle, tumor angiogenesis, and immune reactivities in various types of malignancies [ 5 , 11 , 12 , 13 , 14 , 15 ]. Numerous factors and molecules have been reported in in vivo and in vitro studies as part of the molecular mechanisms underlying the anti-cancer properties of fucoidan.…”