Anti-tumor effects and mechanisms of Astragalus membranaceus (AM) and its specific immunopotentiation: Status and prospect

Abstract

With cancer deaths increasing, the initiation, pathophysiology and curative management of cancer is receiving increasing attention. Traditional therapies such as surgery and chemoradiotherapy are often accompanied by suppression of host immunity, which increase the risk of metastasis. Astragalus membranceus (AM) is commonly utilized as one herbal medicine of traditional Chinese medicines (TCMs) with a variety of biological activities. Studies have shown that the active ingredients of AM and AM-based TCMs, combined with chemotherapy, can enhance anti-tumor efficacy in cancer patients, in addition to reduce complications and avoid side effects induced by chemotherapy. By using various cancer models and cell lines, AM has been found to be capable of shrinking or stabilizing tumors by direct anti-proliferation or pro-apoptosis effect on tumor cells. Further, AM ameliorates immunosuppression by activating M1 macrophages and T cells tumor-kill function in tumor microenvironment (TME). AM is also found to improve systemic immunity which may help promoting efficacy of chemotherapy and preventing metastasis. Thereby this review contributes to an understanding of AM as an adjunctive therapy in the whole course of cancer treatment, at the same time providing useful information for development of more effective anti-tumor medication. The combination of AM and immune checkpoint therapies has a promising therapeutic prospect, and the observation of direct efficacy and mechanisms on tumor growth and metastasis of AM combined with chemotherapies or other therapies require more in vivo validations and further clinical investigation as well.

Introduction

With the rapid growth and aging of the global population, cancer has become increasingly prominent as a leading cause of death (Bray et al., 2018). It is predicted that the incidence of all cancer cases will increase from 12.7 million new cases in 2008 to 22.2 million in 2030 (Bray et al., 2012). Therefore, cancer occurrence, pathophysiology and therapeutic option development are receiving increased attention worldwide, especially in low- and middle-income countries such as China.

Traditional therapies such as surgery and chemoradiotherapy can directly act on cancer cells while have several serious drawbacks. Firstly, most cancer patients are diagnosed too late to perform surgery. Even if there are surgical indications, a series of complications such as bleeding, infection, lymphedema may occur after surgery. Secondly, although chemoradiotherapy is still the main adjuvant therapy to surgery or the preferred treatment for patients with advanced malignant tumors, there are also many side effects and complications, such as bone marrow suppression, impaired liver and kidney function, nausea and vomiting or local radiotherapy damage. More importantly, several regularly used chemotherapeutic drugs convert cancer cells into cancer stem cells, thereby resulting in therapeutic resistance and accelerating cancer cell metastasis by worsening host immunity (Martins-Neves et al., 2016; Safa et al., 2015).

Accumulating evidence has confirmed that cancer cells reside in a specialized microenvironment, or niche, namely the TME. Tumor cells must recruit and reprogram the surrounding normal cells to serve as contributors so that ensure their rapid proliferation, survival, local invasion and remote metastasis (Casey et al., 2015). With tumor development, there is a dynamic alteration on molecular and cellular processes in TME involving the interactions between cancer cells and immune cells. Given the effectiveness of T cells in mediating anti-tumor immune responses, T cell-based immunotherapy is considered as an important and promising therapeutic approach against cancer (Chen and Mellman, 2017). However, the majority of patients treated with immune monotherapies fail to achieve the desired therapeutic response. The main reasons could be the severe immune-suppressive microenvironment including impaired antigen presentation capability in tumor sites that inhibit the proliferation, migration and survival of infiltrating T cells. How to improve the host immune status is therefore very important in T cell-based immunotherapy (Nicolas-Boluda and Donnadieu, 2019).

Astragalus membranaceus (AM, Huang qi in Chinese) is a plant belong to the leguminous family. AM particularly its dry root Astragali Radix, is a popular tonic in traditional Chinese medicine (TCM). It has been found to have multiple biofunctions, such as immunomodulatory, anti-hyperglycemic, anti-inflammatory, anti-oxidant and anti-viral activities (Shao et al., 2004). Modern pharmacological evidence has shown that AM and its active ingredients have strong anti-tumor activity and enhance host immune function. Thus, this review will summarize the capability of AM to reduce the side effects and complications and increase the anti-tumor efficacy caused by chemotherapy in cancer patients. Meanwhile, the mechanism evidences that AM directly shrinks focus or stabilizes cancer state, enhancing the organic immunity to improve the efficacy of chemotherapy and prevent metastasis in a variety of pathways will be accumulated, providing a systematic review and evaluation of the anti-tumor effects and mechanisms of AM. More importantly, the evidence of AM being able to regulate the tumor immune microenvironment (TIME) will be provided, highlighting the multiple anti-tumor targets and signaling pathways of AM as an immunity enhancer, may act as a booster for checkpoint immunotherapy and chemotherapy.