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1.
Front Pharmacol ; 13: 774440, 2022.
Article in English | MEDLINE | ID: mdl-35496272

ABSTRACT

In the tumor microenvironment (TME), the activation of programmed death-1 (PD-1)-programmed death ligand-1 (PD-L1) pathway is one of the main signals of immune escape and tumor deterioration. Clinically, the application of monoclonal antibodies slows down the progression of various malignancies and prolongs the survival of patients effectively. However, these treatments result in serious immune-related adverse events (irAEs) owning to systemic immune activation. Therefore, to achieve long-term therapeutic effects and low side effects, it is necessary to find drugs inhibiting the local PD-1/PD-L1 signaling pathway of the TME. Here, we discovered that Platycodon grandiflorum (PG), a medicine and food homology herb, reduced the expression of PD-1 on the surface of CD8+ T cells to exert antitumor effects in non-small cell lung cancer (NSCLC). Firstly, by combining systems pharmacology strategies and clinical data analysis, we found that PG has the potential to immunomodulate T cells and suppress tumors. Secondly, in vivo and in vitro experiments have confirmed the antitumor effect of the combination of Platycodin D and Platycodin D3, which is preferred and representative of the compounds. Mechanistically, PG increased the infiltration and killing activity of CD8+ T cells, which was related to the decrease of PD-1+ CD8+ T cells. Furthermore, we confirmed that PG regulated the expression of PD-1 on the surface of CD8+ T cells via reducing the secretion of VEGF-A regulated by the level of P-STAT3 in tumor cells. Additionally, PG also positively impacted the biological processes downstream of STAT3. Overall, we demonstrated that PG-mediated downregulation of PD-1 on the surface of CD8+ T cells represents a promising strategy to locally enhance T-cell responses and improve antitumor immunity.

2.
Cancer Cell Int ; 21(1): 529, 2021 Oct 12.
Article in English | MEDLINE | ID: mdl-34641869

ABSTRACT

BACKGROUND: Targeting tumor microenvironment (TME) may provide therapeutic activity and selectivity in treating cancers. Therefore, an improved understanding of the mechanism by which drug targeting TME would enable more informed and effective treatment measures. Glycyrrhiza uralensis Fisch (GUF, licorice), a widely used herb medicine, has shown promising immunomodulatory activity and anti-tumor activity. However, the molecular mechanism of this biological activity has not been fully elaborated. METHODS: Here, potential active compounds and specific targets of licorice that trigger the antitumor immunity were predicted with a systems pharmacology strategy. Flow cytometry technique was used to detect cell cycle profile and CD8+ T cell infiltration of licorice treatment. And anti-tumor activity of licorice was evaluated in the C57BL/6 mice. RESULTS: We reported the G0/G1 growth phase cycle arrest of tumor cells induced by licorice is related to the down-regulation of CDK4-Cyclin D1 complex, which subsequently led to an increased protein abundance of PD-L1. Further, in vivo studies demonstrated that mitigating the outgrowth of NSCLC tumor induced by licorice was reliant on increased antigen presentation and improved CD8+ T cell infiltration. CONCLUSIONS: Briefly, our findings improved the understanding of the anti-tumor effects of licorice with the systems pharmacology strategy, thereby promoting the development of natural products in prevention or treatment of cancers.

3.
Biomed Pharmacother ; 143: 112105, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34560533

ABSTRACT

Although the main focus of immuno-oncology has been manipulating the adaptive immune system, tumor associated macrophages (TAMs) are the main infiltrating component in the tumor microenvironment (TME) and play a critical role in cancer progression. TAMs are mainly divided into two different subtypes: macrophages with antitumor or killing activity are called M1 while tumor-promoting or healing macrophages are named M2. Therefore, controlling the polarization of TAMs is an important strategy for cancer treatment, but there is no particularly effective means to regulate the polarization process. Here, combined systems pharmacology targets and pathways analysis strategy, we uncovered Scutellariae Radix (SR) has the potential to regulate TAMs polarization to inhibit the growth of non-small cell lung cancer (NSCLC). Firstly, systems pharmacology approach was used to reveal the active components of SR targeting macrophages in TME through compound target prediction and target-microenvironment phenotypic association analysis. Secondly, in vitro experiment verified that WBB (wogonin, baicalein and baicalin), major active ingredients of SR are significantly related to macrophages and survival, initiated macrophages programming to M1-like macrophages to promoted the apoptosis of tumor cells. Finally, we evidenced that WBB effectively inhibited tumor growth in LLC (Lewis lung carcinoma) tumor-bearing mice and increased the infiltration of M1-type macrophages in TME. Overall, the systems pharmacology strategy offers a paradigm to understand the mechanism of polypharmacology of natural products targeting TME.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Immunity, Innate/drug effects , Lung Neoplasms/drug therapy , Network Pharmacology , Tumor-Associated Macrophages/drug effects , Animals , Apoptosis/drug effects , Carcinoma, Lewis Lung/immunology , Carcinoma, Lewis Lung/metabolism , Carcinoma, Lewis Lung/pathology , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Coculture Techniques , Databases, Genetic , Female , Humans , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Inbred C57BL , Phenotype , RAW 264.7 Cells , Tumor Burden/drug effects , Tumor Microenvironment , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism
4.
Brief Bioinform ; 22(5)2021 09 02.
Article in English | MEDLINE | ID: mdl-33876189

ABSTRACT

Targeting tumor microenvironment (TME), such as immune checkpoint blockade (ICB), has achieved increased overall response rates in many advanced cancers, such as non-small cell lung cancer (NSCLC), however, only in a fraction of patients. To improve the overall and durable response rates, combining other therapeutics, such as natural products, with ICB therapy is under investigation. Unfortunately, due to the lack of systematic methods to characterize the relationship between TME and ICB, development of rational immune-combination therapy is a critical challenge. Here, we proposed a systems pharmacology strategy to identify resistance regulators of PD-1/PD-L1 blockade and develop its combinatorial drug by integrating multidimensional omics and pharmacological methods. First, a high-resolution TME cell atlas was inferred from bulk sequencing data by referring to a high-resolution single-cell data and was used to predict potential resistance regulators of PD-1/PD-L1 blockade through TME stratification analysis. Second, to explore the drug targeting the resistance regulator, we carried out the large-scale target fishing and the network analysis between multi-target drug and the resistance regulator. Finally, we predicted and verified that oxymatrine significantly enhances the infiltration of CD8+ T cells into TME and is a powerful combination agent to enhance the therapeutic effect of anti-PD-L1 in a mouse model of lung adenocarcinoma. Overall, the systems pharmacology strategy offers a paradigm to identify combinatorial drugs for ICB therapy with a systems biology perspective of drug-target-pathway-TME phenotype-ICB combination.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic/drug effects , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Plant Extracts/therapeutic use , Alkaloids/pharmacology , Alkaloids/therapeutic use , Animals , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , Drug Therapy, Combination , Female , Gene Regulatory Networks/drug effects , Gene Regulatory Networks/genetics , Humans , Immune Checkpoint Inhibitors/pharmacology , Kaplan-Meier Estimate , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mice, Inbred C57BL , Plant Extracts/pharmacology , Quinolizines/pharmacology , Quinolizines/therapeutic use , Sophora/chemistry , Treatment Outcome , Tumor Microenvironment/drug effects , Tumor Microenvironment/genetics
5.
Aging (Albany NY) ; 13(2): 2912-2940, 2021 01 17.
Article in English | MEDLINE | ID: mdl-33460401

ABSTRACT

The clinical notably success of immunotherapy fosters an enthusiasm in developing drugs by enhancing antitumor immunity in the tumor microenvironment (TME). Epimedium, is a promising herbal medicine for tumor immunotherapy due to the pharmacological actions in immunological function modulation and antitumor. Here, we developed a novel systems pharmacology strategy to explore the polypharmacology mechanism of Epimedium involving in targeting TME of non-small cell lung cancer (NSCLC). This strategy integrates the active compounds screening, target predicting, network pharmacology analysis and onco-immune interacting to predict the potential active compounds that trigger the antitumor immunity. Icaritin (ICT), a major active ingredient of Epimedium, was predicted to have good drug-like properties and target immune microenvironment in NSCLC via regulating multiple targets and pathways. Then, we evidenced that the ICT effectively inhibited tumor growth in LLC tumor-bearing mice and increases the infiltration of CD8+ T cells in TME. In addition, we demonstrated that ICT promotes infiltration of CD8+ T cells in TME by downregulating the immunosuppressive cytokine (TNF-α, IL10, IL6) and upregulating chemotaxis (CXCL9 and CXCL10). Overall, the systems pharmacology strategy offers an important paradigm to understand the mechanism of polypharmacology of natural products targeting TME.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Epimedium , Lung Neoplasms/drug therapy , Plant Extracts/pharmacology , T-Lymphocytes, Cytotoxic/drug effects , Tumor Microenvironment/drug effects , Animals , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Movement/drug effects , Cytokines/metabolism , Humans , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Mice , Plant Extracts/therapeutic use , T-Lymphocytes, Cytotoxic/immunology , Tumor Microenvironment/immunology
6.
Phytomedicine ; 79: 153326, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32992083

ABSTRACT

BACKGROUND: Lung cancer is the most common and mortal cancer worldwide. Rhodiola rosea L. (RR), a well-known traditional Chinese medicine (TCM), has been turned out to be effective in anti-lung cancer therapy, but its molecular mechanism of action has not been clearly understood. PURPOSE: In this study, we aimed to elucidate the possible molecular mechanism underlying the effect of RR against non-small cell lung cancer (NSCLC) by systems pharmacology. METHODS: The effects of RR on NSCLC were examined in Lewis lung carcinoma (LLC) tumor-bearing mice models. The possible molecular mechanism was unraveled by systems pharmacology, which includes pharmacokinetics evaluation, active compounds screening, target prediction and network analysis. Cell proliferation was examined by cell counting kit-8 (CCK-8) assay; cell apoptosis was detected by flow cytometry; protein and proinflammatory cytokines expression were evaluated by Western blot and qRT-PCR. RESULTS: In vivo, RR significantly inhibited the tumor growth and prolonged the survival of the tumor bearing mice. In silico, we identified 19 potential active molecules (e.g., salidroside and rhodiosin), 112 targets (e.g., COX-2 and AKT) and 27 pathways (e.g., PI3K/AKT signaling pathway and NF-κB signaling pathway) for RR. Additionally, targets analysis and networks construction further revealed that RR exerted anti-cancer effects by regulating apoptosis, angiogenesis and inflammation. In vitro, salidroside could significantly decrease expression of pro-angiogenic factors (e.g., VEGF and eNOS) and proinflammatory cytokines (e.g., COX-2, iNOS and TNF-α). Also, Bcl-2, an anti-apoptotic protein was decreased whereas Bax, a pro-apoptotic protein, was increased. Further flow cytometry analysis showed that salidroside could induce apoptosis in H1975 cells. CONCLUSIONS: Mechanistically, the antitumor effect of RR on NSCLC was responsible for the synergy among anti-inflammatory, anti-angiogenic and pro-apoptotic.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Screening Assays, Antitumor/methods , Lung Neoplasms/drug therapy , Rhodiola/chemistry , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacokinetics , Apoptosis/drug effects , Biological Availability , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/pathology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Proliferation/drug effects , Flavonoids/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Glucosides/pharmacology , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mice , Mice, Inbred C57BL , Monosaccharides/pharmacology , Phenols/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , RAW 264.7 Cells , Signal Transduction/drug effects , Transcription Factor RelA
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