Huang Shi, Chen Yan, Pan Lingyu, Fei Changyi, Wang Ni, Chu Furui, Peng Daiyin, Duan Xianchun, Wang Yongzhong
The First Affiliated Hospital of Anhui University of Chinese Medicinee, Hefei, China.
College of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
Front Oncol. 2021 Aug 26;11:731522. doi: 10.3389/fonc.2021.731522. eCollection 2021.
Tao Hong Si Wu Decoction (THSWD) is a well-known traditional Chinese medicine used clinically alone or combined with drugs to treat breast cancer. However, there has been no study to date on the underlying mechanisms of its therapeutic effects.
To explore the potential mechanism of THSWD for the treatment of breast cancer using network pharmacology and experimental research.
The active ingredients of THSWD were screened according to Lipinski's rule of five based on the 107 ingredients of THSWD identified by UPLC-Q-TOF-MS. The targets of THSWD and breast cancer from multiple databases were collected, and a Compound-Target-Pathway network based on protein-protein interaction (PPI) was constructed. Gene ontology (GO) analysis and KEGG pathway analysis were performed the DAVID server. Molecular docking studies verified the selected key ingredients and key targets. The results of network pharmacology were verified by experiments. Including the effects of THSWD drug-containing rat serum (THSWD serum) on cell proliferation, and on the targets HRAS, MAPK1, AKT1, GRB2, and MAPK14 were assayed by RT-qPCR and Western blot assays.
In total, 27 active ingredients including 8 core components, were obtained from 107 ingredients and 218 THSWD target genes for the treatment of breast cancer were identified. THSWD is active in the treatment of breast cancer by targeting Ras, FoxO, PI3K-Akt and other signaling pathways. MCF-7 and MDA-MB-231 cell proliferation was inhibited by THSWD serum in a time and concentration dependent manner. THSWD could regulated the RNA and protein expression of core targets HRAS, MAPK1, AKT1, GRB2, and MAPK14 for treatment of breast cancer.
The results of network pharmacology study showed that THSWD is active against breast cancer by intervening with multiple targets and pathways. Luteolin, kaempferol, senkyunolide E, and other 8 compounds may be the core active ingredients of THSWD in the treatment of breast cancer. THSWD treatment of breast cancer may be related to targeting Ras, FoxO, PI3K-Akt, and other signal pathways associated with the core targets HRAS, MAPK1, AKT1, GRB2, and MAPK14.
桃红四物汤（THSWD）是一种著名的传统中药，临床上单独使用或与其他药物联合用于治疗乳腺癌。然而，迄今为止尚未有关于其治疗作用潜在机制的研究。
采用网络药理学和实验研究方法探索桃红四物汤治疗乳腺癌的潜在机制。
基于超高效液相色谱-四极杆飞行时间质谱（UPLC-Q-TOF-MS）鉴定的107种桃红四物汤成分，根据Lipinski的五规则筛选其活性成分。从多个数据库收集桃红四物汤和乳腺癌的靶点，并构建基于蛋白质-蛋白质相互作用（PPI）的化合物-靶点-通路网络。使用DAVID服务器进行基因本体（GO）分析和京都基因与基因组百科全书（KEGG）通路分析。分子对接研究验证了所选的关键成分和关键靶点。通过实验验证网络药理学的结果。包括含桃红四物汤大鼠血清（THSWD血清）对细胞增殖的影响，并通过逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹法检测靶点HRAS、丝裂原活化蛋白激酶1（MAPK1）、蛋白激酶B（AKT1）、生长因子受体结合蛋白2（GRB2）和丝裂原活化蛋白激酶14（MAPK14）。
从107种成分中总共获得了27种活性成分，包括8种核心成分，并鉴定出218个用于治疗乳腺癌的桃红四物汤靶基因。桃红四物汤通过靶向Ras、叉头框蛋白O（FoxO）、磷脂酰肌醇-3激酶-蛋白激酶B（PI3K-Akt）等信号通路对乳腺癌具有治疗活性。THSWD血清以时间和浓度依赖性方式抑制MCF-7和MDA-MB-231细胞增殖。桃红四物汤可调节治疗乳腺癌的核心靶点HRAS、MAPK1、AKT1、GRB2和MAPK14的RNA和蛋白质表达。
网络药理学研究结果表明，桃红四物汤通过干预多个靶点和通路对乳腺癌具有活性。木犀草素、山奈酚、川芎内酯E等8种化合物可能是桃红四物汤治疗乳腺癌的核心活性成分。桃红四物汤治疗乳腺癌可能与靶向Ras、FoxO、PI3K-Akt等信号通路以及核心靶点HRAS、MAPK1、AKT1、GRB2和MAPK14有关。
