Introduction

The combination of the roots of ginseng and Salvia miltiorrhiza is an effective approach for treating metastatic cancer in patients with Qi stagnation and blood stasis patterns. However, the molecular mechanism underlying the combined use of ginseng and Salvia miltiorrhiza is unknown.

Objectives

This study unveils the pharmacological foundation of ginseng and Salvia miltiorrhiza by examining the involvement of neutrophils in the critical process of tumor hematogenous metastasis. Additionally, by employing a reverse pharmacology research model (effect–target–constituent), potential potent components were screened, and the dominant component formulations were determined.

Methods

An experimental lung metastatic model was constructed to compare the antitumor effects of ginseng and Salvia miltiorrhiza. RNA sequencing was employed to identify pivotal biological events and key targets, while the detection of CD62E expression and neutrophil extracellular traps (NETs) release was used to screen for effective substances in ginseng and Salvia miltiorrhiza. In addition, a comprehensive array of in vitro and in vivo experiments was conducted to explore the underlying mechanisms and therapeutic significance.

Results

Compared with single-herb use, the use of ginseng or Salvia miltiorrhiza significantly reduced tumor metastasis, which was accompanied by reduced neutrophil infiltration into the lungs. Cryptotanshinone (CPT), an active constituent of Salvia miltiorrhiza, can inhibit neutrophil adhesion and recruitment to lung tissue by downregulating the expression of E-selectin (CD62E) in endothelial cells. Moreover, the ginseng −derived ginsenoside Rg1 mitigated the formation of NETs in lung tissues and reversed the protumor effects of NETs. We further explored the efficacy of combination therapy with Rg1 and CPT, which also reduced tumor metastasis in vivo.

Conclusion

Ginseng and Salvia miltiorrhiza exhibited a mutual potentiation of the anti-metastatic effect by suppressing both early and late stages of neutrophil-initiated metastasis cascade. Rg1 and CPT represent the synergistic ingredients from ginseng and Salvia miltiorrhiza, respectively.

中文翻译：

---

通过抑制 CD62E 依赖性中性粒细胞浸润和 NET 形成，协同增强人参-丹参草药对及其生物成分的抗转移作用

 介绍

人参根与丹参合用是治疗气滞血瘀患者转移性癌症的有效方法。然而，人参和丹参联合使用的分子机制尚不清楚。

 目标

本研究通过检查中性粒细胞在肿瘤血行转移关键过程中的参与，揭示了人参和丹参的药理学基础。此外，通过采用逆向药理学研究模型 （效应 - 靶点 - 成分），筛选了潜在的有效成分，并确定了主要成分配方。

 方法

构建实验性肺转移模型，比较人参和丹参的抗肿瘤效果。采用 RNA 测序确定关键生物学事件和关键靶点，同时检测 CD62E 表达和中性粒细胞胞外陷阱 （NETs） 释放用于筛选人参和丹参中的有效物质。此外，还进行了一系列全面的体外和体内实验，以探索潜在的机制和治疗意义。

 结果

与单一草药使用相比，使用人参或丹参可显着减少肿瘤转移，同时减少中性粒细胞浸润到肺部。隐丹参酮 （CPT） 是丹参的一种活性成分，可通过下调内皮细胞中 E-选择素 （CD62E） 的表达来抑制中性粒细胞粘附和向肺组织的募集。此外，人参衍生的人参皂甙 Rg1 减轻了肺组织中 NETs 的形成，并逆转了 NETs 的促肿瘤作用。我们进一步探讨了 Rg1 和 CPT 联合治疗的疗效，这也减少了体内肿瘤转移。

 结论

人参和丹参通过抑制中性粒细胞引发的转移级联反应的早期和晚期表现出抗转移作用的共同增强。Rg1 和 CPT 分别代表人参和丹参的协同成分。