Because triple-negative breast cancer (TNBC) lacks expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, it is difficult to treat effectively, and unfortunately, patients with this subtype of breast cancer have the lowest overall survival rates compared with all other breast cancer types. Currently, the treatment of metastatic TNBC is limited to surgery, chemotherapy, and radiotherapy, and still faces chemotherapy resistance and high recurrence, metastasis, and mortality rates. Therefore, there is an urgent need to identify systematic therapeutic regimens, supplements, and novel targets to enhance clinical use.

Fucoidan, conversely, is a polysaccharide found in abundance in brown algae and exhibits a wide array of biological activities, including anti-inflammatory, antitumor, antiviral, anticoagulant, antithrombotic, antiobesity, and antiangiogenic properties. As an immunomodulator, fucoidan can activate natural killer cells, macrophages, and cytotoxic T cells, enhancing the effectiveness of chemotherapy against tumor growth.

Laminaria japonica, a type of brown seaweed, is the source of oligo fucoidan (LMF), a sulfated polysaccharide with a high fucose content and low molecular weight.

First, using the 4T1 syngeneic mouse model, we investigated the therapeutic effects of olaparib and oligo fucoidan supplementation on TNBC aggressiveness and microenvironment.

Olaparib is a potent PARP inhibitor that blocks DNA damage repair and induces synthetic lethality in BRCA1/2 mutation carriers.

Researchers performed clonogenic assays and found that MDA-MB-231 cell proliferation was significantly inhibited by olaparib (See Figure. 1A) and oligofucoidan (See Figure. 1B) administration in a dose-dependent manner. The combination of olaparib and oligo fucoidan resulted in a higher inhibition rate of cell colony formation than monotherapy in different TNBC cell lines (4T1, HCC1395, MDA-MB-231) (Figure. 1C). Olaparib treatment not just stopped the growth of mammospheres (Refer to Figure 1D) but also decreased the levels of cancer stemness markers like EpCAM, Nanog, and Sox2 (Shown in Figure. 2E). Similarly, oligo fucoidan treatment dose-dependently prevented mammosphere formation (See Figure. 2F) and reduced BCSC characteristics of upregulating CD24 and downregulating CD44 and Snail expression (See Figure. 1G).

Olaparib treatment increased sub-G1 cell death and G2/M arrest in TNBC cells, and these effects were enhanced when oligofucoidan was added to the treatment of TNBC cells. Increased expression of Rad51 and programmed cell death ligand 1 (PD-L1), in conjunction with the heightened activation states of epidermal growth factor receptor (EGFR) and adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), are strongly implicated in the promotion of both drug resistance mechanisms and the metastatic spread characteristic of triple-negative breast cancer (TNBC). However, the combination of olaparib and oligofucoidan synergistically reduced Rad51 and PD-L1 levels, as well as EGFR and AMPK activity, consistently inhibiting TNBC cytotoxicity and stemness. Oligo fucoidan and olaparib together were more effective than either drug alone at suppressing the growth of TNBC stem cell spheroids and decreasing the numbers of CD44high/CD24low and EpCAMhigh cells.

The combined effect of oligo fucoidan and olaparib was a crucial suppression of the oncogenic interleukin-6 (IL-6)/p-EGFR/PD-L1 pathway, along with reduced glucose uptake and lactate production. The anti-tumor effects of oligo fucoidan were enhanced by its ability to promote M1 macrophages and reduce the immunosuppressive and tumor-promoting M2 macrophages induced by olaparib. Furthermore, the combination of olaparib and oligo fucoidan dramatically suppressed M2 macrophage infiltration and repolarized M2 to M0-like (F4/80high) and M1-like (CD80high and CD86high) phenotypes. Furthermore, in TNBC cells pretreated with olaparib and oligo fucoidan, M0 macrophages polarized to CD80(+) M1 macrophages, but not to CD163(+) M2 macrophages. It is important to highlight that supplementing orally administered olaparib with oligo fucoidan in mice resulted in higher levels of cytotoxic T cells in the lymphatic system and lower levels of regulatory T cells and M2 macrophages in the tumor, thus inhibiting TNBC recurrence and metastasis post-surgery.

The novel therapeutic strategy of combining olaparib with the natural compound oligo fucoidan offers a promising approach to tackling cancer by reprogramming cancer stemness, metabolism, and the tumor microenvironment, thereby preventing both local recurrence after surgery and distant metastasis.

Source: J Biomed Sci. 2022 Sep 15;29:70. doi: 10.1186/s12929-022-00855-6