Therapeutic Effect and Mechanism of Bushen-Jianpi-Jiedu Decoction Combined with Chemotherapeutic Drugs on Postoperative Colorectal Cancer.

Meng-Die Yang,Jian Chen,Qing Ji,Wen-Hai Wang,Qi Li,Shi-Bing Su,Xiao-Le Chen,Wen-Jun Zhou

doi:10.3389/fphar.2021.524663

Abstract

There is a lack of effective therapeutic drugs in patients with postoperative colorectal cancer (PCRC). This study aimed to investigate the therapeutic effect and mechanisms of Bushen-Jianpi-Jiedu decoction (BSJPJDD) combined with chemotherapeutic drugs (oxaliplatin) on PCRC with liver and kidney yin deficiency and spleen deficiency syndrome (LKYD-SDS) through the therapeutic evaluation of clinical therapy and the integrative analysis of network pharmacology, RNA-seq and label-free data, and experiment verification in vitro. In clinical therapy, the median progression-free survival (PFS) and Karnofsky performance score (KPS) were increased in PCRC patients by the aqueous extract of BSJPJDD combined with oxaliplatin treatment for three months, compared to oxaliplatin alone (p < 0.05). The integrative analysis showed that 559 differentially expressed genes (DEGs) and 11 differentially expressed proteins (DEPs) were regulated by BSJPJDD, among which seven bioactive compounds through 39 potential targets were involved in the regulation of multiple signaling pathways including MAPK, PI3K-Akt, and HIF-1, etc. In the experimental verification, an ELISA assay showed that plasma ZEB2, CAT, and KRT78 were decreased, and IL-1Α, CD5L, FBLN5, EGF, and KRT78 were increased in comparison to the above (p < 0.05). Furthermore, the SW620 cell viability was inhibited and the expressions of MAPK and the p-ERK/ERK ratio were significantly downregulated by the aqueous extract of BSJPJDD combined with oxaliplatin treatment, compared with oxaliplatin treatment alone (p < 0.05). These data suggested that BSJPJDD combined with oxaliplatin prolongs the survival and improves Karnofsky performance status of PCRC patients with LKYD-SDS, and may be associated with the regulation of multiple signaling pathways.

Highlights

Colorectal cancer (CRC), one of the most common cancers in the world, has become the third and second leading cause of cancer death among men and women, respectively (Barzi et al, 2017; Chen et al, 2017; Bos et al, 2018)
Our study showed that Bushen-Jianpi-Jiedu decoction (BSJPJDD) combined with oxaliplatin prolongs the survival and improves the life quality of postoperative colorectal cancer (PCRC) patients with LKYD-SDS, and its pharmacological mechanisms may be involved in the comprehensive regulation of multi-compounds, multi-targets, and multi-pathways
The Karnofsky performance score (KPS) in advanced stage in the BSJPJDD group was significantly increased compared to the control group (p < 0.05). These results indicated that BSJPJDD may increase the efficacy of oxaliplatin, improve the survival time and Karnofsky performance status of PCRC patients with LKYD-SDS

Summary

Introduction

Colorectal cancer (CRC), one of the most common cancers in the world, has become the third and second leading cause of cancer death among men and women, respectively (Barzi et al, 2017; Chen et al, 2017; Bos et al, 2018). Most patients of CRC are diagnosed at clinical stages II-III (Bos et al, 2018). The use of chemotherapy alone is insufficient, as there are adverse reactions to chemotherapy; the poor tolerance of patients and chemotherapy resistance (Panczyk, 2014; Li et al, 2019), an adjuvant therapy of postoperative chemotherapy is needed. The higher the score, the better health condition, and the more the body can tolerate the side effects of treatment with a higher quality of life. It has been reported that traditional Chinese medicine (TCM) combined with chemotherapy can improve CRC treatment, through reducing postoperative ileus and urinary, improving the tolerance of patients and the complications and resistance of chemotherapy, remodeling the gut microbiota and the tumor microenvironment, suppressing thymidylate synthase, and preventing cancer recurrence and metastasis, etc. It has been reported that traditional Chinese medicine (TCM) combined with chemotherapy can improve CRC treatment, through reducing postoperative ileus and urinary, improving the tolerance of patients and the complications and resistance of chemotherapy, remodeling the gut microbiota and the tumor microenvironment, suppressing thymidylate synthase, and preventing cancer recurrence and metastasis, etc. (Tan et al, 2008; Ye et al, 2015; Liu et al, 2017a; Sui et al, 2017; Liu et al, 2018a; Zhang et al, 2018; Lv et al, 2019; Hong et al, 2020)

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