Oligo-Fucoidan supplementation enhances the effect of Olaparib on preventing metastasis and recurrence of triple-negative breast cancer in mice

Abstract

Background: Seaweed polysaccharides have been recommended as anticancer supplements and for boosting human health; however, their benefits in the treatment of triple-negative breast cancers (TNBCs) and improving immune surveillance remain unclear. Olaparib is a first-in-class poly (ADP-ribose) polymerase inhibitor. Oligo-Fucoidan, a low-molecular-weight sulfated polysaccharide purified from brown seaweed (Laminaria japonica), exhibits significant bioactivities that may aid in disease management.Methods: Macrophage polarity, clonogenic assays, cancer stemness properties, cancer cell trajectory, glucose metabolism, the TNBC 4T1 cells and a 4T1 syngeneic mouse model were used to inspect the therapeutic effects of olaparib and Oligo-Fucoidan supplementation on TNBC aggressiveness and microenvironment.Results: Olaparib treatment increased sub-G1 cell death and G2/M arrest in TNBC cells, and these effects were enhanced when Oligo-Fucoidan was added to treat the TNBC cells. The levels of Rad51 and programmed deathligand 1 (PD-L1) and the activation of epidermal growth factor receptor (EGFR) and adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) facilitate drug resistance and TNBC metastasis. However, the combination of olaparib and Oligo-Fucoidan synergistically reduced Rad51 and PD-L1 levels, as well as the activity of EGFR and AMPK; consistently, TNBC cytotoxicity and stemness were inhibited. Oligo-Fucoidan plus olaparib better inhibited the formation of TNBC stem cell mammospheroids with decreased subpopulations of CD44 high /CD24 low and EpCAM high cells than monotherapy. Importantly, Oligo-Fucoidan plus olaparib repressed the oncogenic interleukin-6 (IL-6)/p-EGFR/ PD-L1 pathway, glucose uptake and lactate production. Oligo-Fucoidan induced immunoactive and antitumoral M1 macrophages and attenuated the side effects of olaparib, such as the promotion on immunosuppressive and protumoral M2 macrophages. Furthermore, olaparib plus Oligo-Fucoidan dramatically suppressed M2 macrophage invasiveness and repolarized M2 to the M0-like (F4/80 high ) and M1-like (CD80 high and CD86 high ) phenotypes. In addition, olaparib-and Oligo-Fucoidan-pretreated TNBC cells resulted in the polarization of M0 macrophages into CD80(+) M1

Prevotella copri exhausts host’s intrinsic indol-3-pyruvid acid to promote breast cancer development: Inactivation of AMPK via UHRF1-mediated negative regulation

“…Although several studies have revealed the paradoxical role of AMPK in carcinogenesis, it has been found that activated AMPK is negatively associated with the development of breast cancer [52,53]. Similarly, we also found that upon the cytotoxicity of IPyA, AMPK in the breast cancer cells was evidently activated accompanying with dramatic reduction of ATP production, and the downstream (mTOR and ULK) was also affected.…”

NOS2 and COX2 Provide Key Spatial Targets that Determine Outcome in ER-Breast Cancer

“…These earlier observations are extended herein by the identification of unique EpCAM + /CD44v6 + cellular neighborhoods that border NOS2/COX2 high regions. Given that EpCAM and CD44v6 are markers of metastasis and cancer stemness, these observations support the role(s) of tumor NOS2/COX2 expression key targets of disease progression in breast and other tumors (27,29). Moreover, the orthogonal expression of tumor NOS2/COX2 in distinct cells and regions within the TME suggest that the spatial configuration of these enzymes has important roles during intercellular communication.…”

NT5DC2 knockdown suppresses progression, glycolysis, and neuropathic pain in triple‐negative breast cancer by blocking the EGFR pathway

“…38 Another study revealed that reduced EGFR activity was associated with the repolarization of macrophages from the M2 phenotype to the M1 phenotype in TNBC. 39 EGFR augments glycolysis in TNBC cells, and the combination of a glycolysis inhibitor and an EGFR inhibitor effectively reduces TNBC cell proliferation. 40 In addition, EGFR inhibitors have been reported to improve neuropathic pain in patients.…”

“…Previous research has revealed that EGFR activation caused an increase in BRAC cell migration and invasion 38 . Another study revealed that reduced EGFR activity was associated with the repolarization of macrophages from the M2 phenotype to the M1 phenotype in TNBC 39 . EGFR augments glycolysis in TNBC cells, and the combination of a glycolysis inhibitor and an EGFR inhibitor effectively reduces TNBC cell proliferation 40 .…”