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. 2022 Mar 15:12:790713.
doi: 10.3389/fonc.2022.790713. eCollection 2022.

Exploration of the Potential Mechanism of Qi Yin San Liang San Decoction in the Treatment of EGFRI-Related Adverse Skin Reactions Using Network Pharmacology and In Vitro Experiments

Yalei Wang  1 , Yali Zhang  1 , Chengcheng Ding  2 , Caixia Jia  1 , Huawei Zhang  1 , Tiantian Peng  3 , Shuo Cheng  1 , Weihang Chen  3 , Yan Tan  2 , Xu Wang  1 , Zhaoheng Liu  2 , Peng Wei  1 , Xue Wang  4 , Miao Jiang  2 , Qian Hua  2
Affiliations

Exploration of the Potential Mechanism of Qi Yin San Liang San Decoction in the Treatment of EGFRI-Related Adverse Skin Reactions Using Network Pharmacology and In Vitro Experiments

Yalei Wang et al. Front Oncol. .

Abstract

Background: Adverse skin reactions are the most common side effects of epidermal growth factor receptor inhibitors (EGFRIs) in the treatment of cancer, significantly affecting the survival rate and quality of life of patients. Qi Yin San Liang San Decoction (QYSLS) comes from folk prescription and is currently used in the clinical treatment of adverse skin reactions caused by EGFRIs. However, its therapeutic mechanism remains unclear.

Objectives: To explore the potential mechanism of QYSLS in the treatment of adverse skin reactions caused by EGFR inhibition using network pharmacology and experimental research.

Methods: First, we verified the effectiveness of QYSLS in vivo using model mice. Second, the related targets of adverse skin reactions associated with EGFR inhibition were predicted by the Gene Expression Omnibus (GEO) database, and effective components and predictive targets of QYSLS were analyzed by Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Batman-TCM databases. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed via the Bioconductor (R) V3.8 bioinformatics software. Molecular docking studies verified the selected key ingredients and targets. Finally, the results of network pharmacology were verified by in vitro experiments.

Results: In the in vivo mouse model, QYSLS effectively reduced the occurrence of skin side effects. Network pharmacological results showed that the active ingredient luteolin, quercetin, licochalcone a, and kaempferol and the effective targets prostaglandin-endoperoxide synthase 2 (PTGS2), matrix metallopeptidase 9 (MMP9), and C-C motif chemokine ligand 2 (CCL2) were related to the interleukin-17 (IL-17) and tumor necrosis factor (TNF) pathway. Subsequently, the related active compounds and targets were verified using HaCaT cells as an in vitro adverse reaction model. The results showed that luteolin and quercetin increased the expression of PTGS2 and MMP9 and reduced the expression of CCL2 in HaCaT cells treated with gefitinib.

Conclusions: The results revealed that QYSLS effectively treats EGFRI-related adverse skin reactions through multi-target and multi-pathway mechanisms. Luteolin and quercetin may be the core active ingredients of QYSLS in the treatment of EGFRI-related adverse skin reactions, and their therapeutic effects are potentially mediated through PTGS2, CCL2, and MMP9 in the IL-17 and TNF signaling pathway.

Keywords: EGFR inhibitor; QYSLS; network pharmacology; skin adverse reaction; traditional Chinese medicine.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flowchart of the network pharmacology and experimental study of QYSLS in the treatment of adverse skin reactions caused by EGFR inhibition.
Figure 2
Figure 2
In vivo experiments showed that QYSLS effectively improved the adverse skin reactions caused by gefitinib. (A) Skin condition of the neck, limbs, face, and lip of mice in each group. (B) H&E staining of skin tissue from mice in each group. (C) Quantitative analysis of skin epidermal thickness. (D) Liver index of mice in each group. (E) Spleen index of mice in each group. “*” compared with Control, *p < 0.05, ****p < 0.0001. “#” compared with Gefitinib, ##p < 0.01, ###p < 0.005, ####p < 0.0001.
Figure 3
Figure 3
Collection of EGFRI-related adverse skin reaction targets. (A) Heat map of the top 40 differentially expressed genes. (B) Volcano map of the top 40 differentially expressed genes.
Figure 4
Figure 4
Ingredient-target network of QYSLS.
Figure 5
Figure 5
Screening of QYSLS-related compounds and construction of component target network. (A) Venn diagram of targets of herbs and diseases. (B) The compound–compound target network for QYSLS in treating EGFRI-related adverse skin reactions.
Figure 6
Figure 6
The disease target-PPI network.
Figure 7
Figure 7
Component target network analysis of QYSLS in the treatment of EGFRI-related adverse skin reactions. (A) GO analysis of biological process, cellular component, and molecular function terms was performed on major targets of QYSLS. (B) KEGG analysis for the major targets of QYSLS. (C) Target-pathway network diagram of KEGG enrichment.
Figure 8
Figure 8
Validation of interactions between QYSLS compounds and targets.
Figure 9
Figure 9
Inhibitory effects of quercetin (A) luteolin (B) licochalcone a (C), and kaempferol (D) on the proliferation of HaCaT cells. The drug concentration–cell viability curve was generated on the basis of cell viability data. All data were expressed as the mean ± SD. “*” compared with Control (The first pillar), ****p < 0.0001. “#” compared with Gefitinib (The second pillar), ###p < 0.005, ####p < 0.0001.
Figure 10
Figure 10
QYSLS mitigated EGFRI-induced adverse skin reactions by regulating the IL-17 and TNF pathway. qPCR was used to detect the mRNA expression levels of PTGS2, CCL2, and MMP9 in mice treated with quercetin (A–C) and luteolin (D–F). “*”compared with Control, ***p < 0.005, ****p < 0.0001. “#”compared with Gefitinib, ##p < 0.01, ###p < 0.005, ####p < 0.0001.
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