Cepharanthine Hydrochloride Improves Cisplatin Chemotherapy and Enhances Immunity by Regulating Intestinal Microbes in Mice.

Pengjun Zhou,Dandan Xu,Ziyao Li,Qi Bai,Rong Zhang,Yue Feng,Yifei Wang,Yao Wang,Guifeng Su,Xiaogang Wang,Huizhong Liu,Pengxiao Chen,Ying Wang

doi:10.3389/fcimb.2019.00225

Abstract

Chemotherapy is one of the major treatment strategies for esophageal squamous cell carcinoma (ESCC). Unfortunately, most chemotherapeutic drugs have significant impacts on the intestinal microbes, resulting in side effects and reduced efficiency. Therefore, new strategies capable of overcoming these disadvantages of current chemotherapies are in urgent need. The natural product, Cepharanthine hydrochloride (CEH), is known for its anticancer and immunoregulatory properties. By sequencing the V4 region of 16S rDNA, we characterized the microbes of tumor-bearing mice treated with different chemotherapy strategies, including with CEH. We found that CEH improved the therapeutic effect of CDDP by manipulating the gut microbiota. Through metagenomic analyses of the microbes community, we identified a severe compositional and functional imbalance in the gut microbes community after CDDP treatment. However, CEH improved the effect of chemotherapy and ameliorated CDDP treatment-induced imbalance in the intestinal microbes. Mechanically, CEH activated TLR4 and MYD88 innate immune signaling, which is advantageous for the activation of the host's innate immunity to exert a balanced intestinal environment as well as to trigger a better chemotherapeutic response to esophageal cancer. In addition, TNFR death receptors were activated to induce apoptosis. In summary, our findings suggest that chemotherapy of CDDP combined with CEH increased the effect of chemotherapy and reduced the side effects on the microbes and intestinal mucosal immunity. We believe that these findings provide a theoretical basis for new clinical treatment strategies.

Highlights

Esophageal squamous cell carcinoma (ESCC) is the main histological type of esophageal cancer, accounting for 90% of all esophageal cancers, and is one of the most common fatal cancers (McGuire, 2016)
In this study, we established a mouse model of xenograft tumors, which mimicked the disturbance state of intestinal microbes treated by CDDP in humans. By using this animal model, we investigated the role of Cepharanthine hydrochloride (CEH) in maintaining the balance of intestinal microbes and host intestinal mucosal immunity during chemotherapy
We found that CEH therapy did not decrease bodyweight; CDDP alone or combined with CEP resulted in significant weight loss (Figure 1B)

Summary

Introduction

Esophageal squamous cell carcinoma (ESCC) is the main histological type of esophageal cancer, accounting for 90% of all esophageal cancers, and is one of the most common fatal cancers (McGuire, 2016). While the incidence of ESCC in men has declined globally, its incidence in women has increased (Wang et al, 2018). Because ESCC is mostly diagnosed in the advanced stages or during metastasis, patients cannot undergo radical surgery. Chemotherapy has a significant impact on the intestinal microbes and may lead to intestinal mucosal inflammation, which is usually caused by intestinal ecological disorders (Montassier et al, 2015; Ichim et al, 2018; Perales-Puchalt et al, 2018). It is important to develop new treatment strategies or drugs for ESCC patients in order to improve the intestinal dysbiosis caused by chemotherapy

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