Angelica sinensis polysaccharides ameliorate 5-flourouracil-induced bone marrow stromal cell proliferation inhibition via regulating Wnt/β-catenin signaling

Hanxianzhi Xiao,Yue Xiang,Lu Wang,Minghe Xiao,Yaping Wang,Rongjia Qi,Ziling Wang

doi:10.32604/biocell.2021.015039

Abstract

Chemotherapy may cause cellular oxidative stress to bone marrow. Oxidative damage of bone marrow hematopoietic microenvironment is closely related to chronic myelosuppression after chemotherapeutic treatment. Angelica sinensis polysaccharides (ASP) are major effective ingredients of traditional Chinese medicine Angelica with multi-target anti-oxidative stress features. In the current study, we investigated the protective roles and mechanisms of ASP on chemotherapy-induced bone marrow stromal cell (BMSC) damage. The human bone marrow stromal cell line HS-5 cells were divided into control group, 5-FU group, 5-FU + ASP group, and 5-FU + LiCl group to investigate the mechanism of ASP to alleviate 5-FU-induced BMSC proliferation inhibition. The results showed that 5-FU inhibits the growth of HS-5 cells in a time and dose-dependent manner; however, ASP partially counteracted the 5-FU-induced decrease in cell viability, whereas Wnt signaling inhibitor Dkk1 antagonized the effect of ASP on HS-5 cells. ASP reversed the decrease in total cytoplasmic β-catenin, p-GSK-3β, and CyclinD1 following 5-FU treatment and modulated nuclear expression of β-catenin, Lef-1, and C-myc proteins. Furthermore, ASP also enhanced the antioxidant capacity of cells and reduced 5-FU-induced oxidative stress, attenuated FoxO1 expression, thus weakened its downstream apoptosis-related proteins and G0/G1 checkpoint-associated p27Kip1 expression to alleviate 5-FU-induced apoptosis and to promote cell cycle progression. All the results above suggest that the protective role of ASP in 5-FU-treated BMSCs proliferation for the chemotherapy may be related to its activating Wnt/β-catenin signaling and keeping homeostasis between β-catenin and FoxO1 under oxidative stress. The study provides a potential therapeutic strategy for alleviating chemotherapeutic damage on BMSCs.

Highlights

Chemotherapy-induced bone marrow hematopoietic microenvironment oxidative damage is closely related to myelosuppression
We demonstrated that Angelica Sinensis Polysaccharides (ASP) alleviated 5-FU-induced stromal cell proliferation inhibition, apoptosis, and oxidative stress damage, and the underlying mechanism may be related to ASP activating Wnt/β-catenin signaling and keeping homeostasis between β-catenin and FoxO1 under oxidative stress
ASP or Lithium chloride (LiCl) administration protected the antioxidant enzymes including Superoxide Dismutase (SOD) and CAT in HS-5 cells (Fig.4D, E). These results demonstrate that 5-FU cause oxidative stress to HS-5 cells, whereas ASP exert a significant anti-oxidative role to alleviate 5-FU-induced oxidative stress, which may be related to the activation of Wnt/β-catenin signaling

Summary

Introduction

Chemotherapy-induced bone marrow hematopoietic microenvironment oxidative damage is closely related to myelosuppression. We investigated the potential benefits and mechanism of action of ASP on chemotherapyinduced bone marrow stromal cell (BMSC) damage. Chemotherapy-induced myelosuppression damage the proliferating hematopoietic progenitors, and affect the stromal cells of hematopoietic microenvironment, and this may be the reason for chronic hematopoietic dysfunction[5,6,7,8,9,10]. It was reported that the mechanism of stromal cells proliferation inhibition and apoptosis after 5-FU treatment is oxidative damage[13, 14]. Our previous findings have confirmed that following oxidative damage of BMSCs 5-FU may alter bioactive substance and cause stress-induced premature senescence (SIPS) of hematopoietic cells[15]. To explore its related mechanisms to reduce the side effects of chemotherapy drugs and to screen protection drugs during chemotherapy is of clinical guidance significance

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