Lu Keqin, Xia Yawen, Cheng Peng, Li Yanan, He Liang, Tao Li, Wei Zhonghong, Lu Yin
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
J Adv Res. 2024 Oct 30. doi: 10.1016/j.jare.2024.10.036.
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.
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.
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.
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.
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.
人参和丹参配伍是治疗气滞血瘀型转移性癌症患者的有效方法。然而，人参和丹参联合使用的分子机制尚不清楚。
本研究通过研究中性粒细胞在肿瘤血行转移关键过程中的作用，揭示人参和丹参的药理基础。此外，采用反向药理学研究模式（效应-靶点-成分），筛选潜在的有效成分，并确定主要成分配方。
构建实验性肺转移模型，比较人参和丹参的抗肿瘤作用。采用RNA测序鉴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，以筛选人参和丹参中的有效物质。此外，还进行了一系列体外和体内实验，以探讨其潜在机制和治疗意义。
与人参或丹参单味药使用相比，联合使用显著降低了肿瘤转移，并伴有肺组织中性粒细胞浸润减少。丹参的活性成分隐丹参酮（CPT）可通过下调内皮细胞中E-选择素（CD62E）的表达，抑制中性粒细胞对肺组织的黏附和募集。此外，人参中的人参皂苷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，其在体内也降低了肿瘤转移。
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相互增强。Rg1和CPT分别代表人参与丹参的协同成分。
