Saponins from Sanguisorba officinalis Improve Hematopoiesis by Promoting Survival through FAK and Erk1/2 Activation and Modulating Cytokine Production in Bone Marrow.

Xin Chen,Jianxin Ji,Bogang Li,Shuang Chen,Zhongliu Wu,Yue Gao

doi:10.3389/fphar.2017.00130

Abstract

Radix Sanguisorbae, the root of Sanguisorba officinalis L. is used as traditional Chinese medicine. In recent decades, it has been reported to be clinically effective against myelosuppression induced by chemotherapy and/ or radiotherapy. However, the underlining mechanism has not been well studied. In this work, we evaluated the hematopoietic effect of total saponins from S. officinalis L. on myelosuppressive mice induced by cyclophosphamide and by60Co-γ-irradiation and confirmed the therapeutic effect. Then, we found total saponins and their characteristic constituents Ziyuglycoside I and Ziyuglycoside II can inhibit apoptosis of TF-1 cells caused by cytokine deprivation, and promote survival of mouse bone marrow nuclear cells through focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1/2 (Erk1/2) activation in vitro. In addition, they can down-regulate macrophage inflammatory protein 2 (MIP-2), platelet factor 4 (PF4) and P-selectin secretion, which are reported to be suppressive to hematopoiesis, both in vitro and in vivo. These results suggest that promotion of survival through FAK and Erk1/2 activation and inhibition of suppressive cytokines in the bone marrow is likely to be the pharmacological mechanism underlying the hematopoietic effect of saponins from S. officinalis L.

Highlights

Patients receiving chemotherapeutic agents and/or ionizing radiation often experience varying degrees of myelosuppression, characterized by the disruption of hematopoietic activity (Barreto et al, 2014)
We found that in the cytokine free group, treatment with total saponins, Ziyuglycoside I and Ziyuglycoside II resulted in a dose-dependent increase in cell viability by up to 73% (±28%), 22% (±9%), and 63% (±11%), respectively, as compared to vehicle-treated control cells, whereas in the presence of cytokines in the medium, treatment by saponins exhibited little improvement in cell viability as compared to vehicle-treated control (Figure 2A)
Using cytokine-deprived TF-1 cells as apoptosis model, we found that total saponins, Ziyuglycoside I and Ziyuglycoside II can reduce apoptosis caused by cytokine deprivation and anti-apoptotic proteins Mcl-1 and survivin were involved in the anti-apoptotic effect of saponins

Summary

Introduction

Patients receiving chemotherapeutic agents and/or ionizing radiation often experience varying degrees of myelosuppression, characterized by the disruption of hematopoietic activity (Barreto et al, 2014). Hematopoiesis is the production of various types of mature blood cells from hematopoietic stem cells within the bone marrow. Saponins from Sanguisorba Promote Hematopoiesis toxicity to tumor cells and rapidly proliferating hematopoietic progenitor cells (Parchment et al, 1998). The anti-tumor therapy causes myelotoxicity indirectly by affecting the bone marrow microenvironment including stromal cells and hematopoietic regulators in the bone marrow. Leukocytes have the shortest half-life in circulation and a decrease in leukocytes count (neutropenia) is a frequently occurring consequence of myelosuppression. Profound myelotoxicity will lead to blood losing events or severe infection presented with sepsis and febrile neutropenia. Cancer treatment-induced hematologic toxicities still are the main reasons of mortality and morbidity throughout the therapy of cancer (Wang et al, 2006)

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