Carboxymethylated and sulfated Cyclocarya paliurus polysaccharides inhibited colon cancer cells growth via PI3K/AKT-MAPKs/NF-κB pathways and immunomodulation

Abstract

Our previous research revealed that carboxymethylation modification (CM-CP) and sulfation modification (S-CP) could enhance the antitumor activity of Cyclocarya paliurus polysaccharides (CP), however, the antitumor mechanisms of CM-CP and S-CP are not fully clarified and remain largely unexplored. The aims of the present study were to investigate the dual anti-tumor function of CM-CP and S-CP in inhibiting cancer cells and activating macrophages to exert immunomodulation. Results revealed that CM-CP and S-CP preferentially inhibited the proliferation of colon cancer CT-26 cells in dose-dependent and time-dependent ways, without toxicity to normal cell lines. Flow cytometry values further established that CM-CP and S-CP interventions elicited acidification in the cells, arrested the cell cycle in S stage, raised the amount of reactive oxygen species and activated oxidative stress. CM-CP and S-CP treatment elicited the depolarization of mitochondrial membranous potentials and Ca2+ superload, and disrupted the equilibrium of Na+/K+-ATPase and Ca2+-ATPase. Simultaneously, apoptotic proteins expression assays revealed that CM-CP and S-CP promoted CT-26 cell apoptosis through PI3K/AKT-MAPKs/NF-κB signal pathways. In parallel, CM-CP and S-CP dramatically promoted the proliferation and secretory activity (TNF-α and NO) of RAW264.7 cells. Co-culture of cancer cells with CM-CP and S-CP-stimulated macrophage supernatants resulted in more pronounced suppression of cancer cell viability. These findings demonstrated that CM-CP and CM-CP not only inhibit cancer cell growth directly, but also activate macrophages to exert immunomodulatory effects to suppress cancer cells. Furthermore, CM-CP and CM-CP make a contribution to the development of potential functional foods or supplements for the prevention or treatments of colorectal cancer.