An effective drug sensitizing agent increases gefitinib treatment by down regulating PI3K/Akt/mTOR pathway and up regulating autophagy in non-small cell lung cancer

Zhang, Jue; Qu, Zhibo; Hong, Ying; Sun, Lingling; Harata-Lee, Yuka; Cui, Jingang; Aung, Thazin Nwe; Liu, Xiaomin; You, Rongli; Wang, Wei; Lü, Hai; Adelson, David L.; Lin, Lizhu

doi:10.1016/j.biopha.2019.109169

Cited by 28 publications

(21 citation statements)

References 48 publications

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“…In a current experiment, transcriptomic analysis of CKItreated non-small cell lung cancer cell lines revealed that CKI does regulate ErbB, MAPK, PI3K/Akt and other pathways. Flow cytometry analysis confirmed that mTOR is located downstream of PI3K/Akt and is the main pathway for CKI to regulate cancer cells [61]. Therefore, these potential targets and pathways may be key for CKI treatment of GC.…”

Section: Discussionmentioning

confidence: 80%

Study on the mechanisms of compound Kushen injection for the treatment of gastric cancer based on network pharmacology

Zhou

Zhu

et al. 2020

BMC Complement Med Ther

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Background: As an effective prescription for gastric cancer (GC), Compound Kushen Injection (CKI) has been widely used even though few molecular mechanism analyses have been carried out. Methods: In this study, we identified 16 active ingredients and 60 GC target proteins. Then, we established a compound-predicted target network and a GC target protein-protein interaction (PPI) network by Cytoscape 3.5.1 and systematically analyzed the potential targets of CKI for the treatment of GC. Finally, molecular docking was applied to verify the key targets. In addition, we analyzed the mechanism of action of the predicted targets by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Results: The results showed that the potential targets, including CCND1, PIK3CA, AKT1, MAPK1, ERBB2, and MMP2, are the therapeutic targets of CKI for the treatment of GC. Functional enrichment analysis indicated that CKI has a therapeutic effect on GC by synergistically regulating some biological pathways, such as the cell cycle, pathways in cancer, the PI3K-AKT signaling pathway, the mTOR signaling pathway, and the FoxO signaling pathway. Moreover, molecular docking simulation indicated that the compounds had good binding activity to PIK3CA, AKT1, MAPK1, ERBB2, and MMP2 in vivo. Conclusion: This research partially highlighted the molecular mechanism of CKI for the treatment of GC, which has great potential in the identification of the effective compounds in CKI and biomarkers to treat GC.

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Section: Discussionmentioning

confidence: 80%

Study on the mechanisms of compound Kushen injection for the treatment of gastric cancer based on network pharmacology

Zhou

Zhu

et al. 2020

BMC Complement Med Ther

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“…Abnormal activation of pathways caused by abnormal expression of these proteins is a critical factor affecting the progression of esophageal cancer. Zhang 57 found that CKI can increase the ability to inhibit lung cancer cell proliferation and increase sensitivity to gefitinib by downregulating the PI3K/AKT pathway. A study has also shown that matrine derivatives, which are one of the main components of CKI, can be downregulated, CCND1, and attenuated the PI3K/Akt pathway to induce G1 cell cycle arrest and autophagy in cancer cells through immunofluorescence analysis, western blotting and murine models 58 .…”

Section: Discussionmentioning

confidence: 99%

Integrated bioinformatics analysis to decipher molecular mechanism of compound Kushen injection for esophageal cancer by combining WGCNA with network pharmacology

Zhou

Zhang

et al. 2020

Sci Rep

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compound Kushen injection (cKi), a medicine in widespread clinical use in china, has proven therapeutic effects on cancer. However, few molecular mechanism analyses have been carried out. To address this problem, bioinformatics approaches combining weighted gene co-expression network analysis with network pharmacology methods were undertaken to elucidate the underlying molecular mechanisms of CKI in the treatment of esophageal cancer (ESCA). First, the key gene modules related to the clinical traits of ESCA were analysed by WCGNA. Based on the results, the hub genes related to CKI treatment for ESCA were explored through network pharmacology. Molecular docking simulation was performed to recognize the binding activity of hub genes with CKI compounds. The results showed that the potential hub targets, including EGFR, ErbB2, CCND1 and IGF1R, are therapeutic targets of CKI for the treatment of ESCA. Moreover, these targets were significantly enriched in many pathways related to cancer and signalling pathways, such as the PI3K-Akt signalling pathway and ErbB signalling pathway. In conclusion, this research partially highlighted the molecular mechanism of CKI in the treatment of ESCA, offering great potential in the identification of the effective compounds in CKI and biomarkers for ESCA treatment. Esophageal cancer (ESCA) is widespread worldwide. According to Global Cancer Statistics 2018, it ranks seventh in incidence and sixth in mortality 1. The 5-year survival rate of ESCA is between 12 and 20% and differs substantially by sex 2. China is a high-risk area for ESCA, especially in some rural areas, where the incidence rate far exceeds that of urban areas due to lifestyle and environmental reasons 3. ESCA can be divided into esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) according to histological classification. In recent decades, the incidence of EAC in Western countries has increased several times, and the proportion of ESCC has exceeded 90% throughout China 4,5. The introduction of chemo(radio)therapy and surgical therapy led to increased survival rates and reduced the incidence of recurrence 6. Because conventional methods do not adequately improve patient survival of ESCA, however, scientists are seeking more effective treatments. Recently, traditional Chinese medicine (TCM) has taken the world stage as complementary and alternative medicine 7. Compound Kushen Injection (CKI) consists of two herbs, Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Smilacis Glabrae). CKI mainly contains various anticancer ingredients, such as matrine and oxymatrine, which can inhibit the growth of tumour cells, overcome resistance to metastasis and multidrug resistance, and protect human immunity 8. CKI has been utilized in clinical practice for decades to treat various solid tumour types, including liver cancer, breast cancer, gastric cancer, and other cancer types 8,9. The analysis of medical data on 2,550 ESCA patients from 22 large-scale hospitals in China confirmed that CKI has been ...

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“…Therefore, we will enlarge the sample size in further research. The PI3K/AKT/mTOR signal pathway plays an important role in many tumors [23][24][25] and is suggested to be significantly activated in MM, and thus promotes the MM progress. 26 Our results have verified that the activation of PI3K/AKT/mTOR signal pathway was found by Western blot assay in patients with MM ( Figure 2D).…”

Section: Discussionmentioning

confidence: 99%

miR‐215‐5p is an anticancer gene in multiple myeloma by targeting RUNX1 and deactivating the PI3K/AKT/mTOR pathway

Liu

Zhang

Huang

et al. 2019

J of Cellular Biochemistry

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This study examined the underlying mechanism of miR‐215‐5p in multiple myeloma (MM) at the molecular level. miR‐215‐5p was upregulated in bone marrow specimens of patients with MM and MM cell lines through real‐time polymerase chain reaction, and downregulation of miR‐215‐5p was related to poor survival of patients with MM. The results of Western blot assay showed that the PI3K/AKT/mTOR signaling pathway was activated in bone marrow specimens of patients with MM. miR‐215‐5p was found to negatively correlate with runt‐related transcription factor 1 (RUNX1) expression in MM clinical bone marrow samples. Therefore, to test the probable mechanisms of the regulation of MM cell proliferation and apoptosis, a miR‐215‐5p mimics/inhibitors/negative control was transfected into MM cells. The targets of miR‐215‐5p were estimated using four bioinformatics databases (including miRDB, miRTarBase, Starbase, and Targetscan). Furthermore, enrichment analyses of gene ontology and Kyoto Encyclopedia of Genomes pathway were carried out at the Enrichr website. Cell viability was detected using the MTT method, while apoptosis and cell cycle were measured using flow cytometry. RUNX1, CDK2, CDC25B, cleaved‐caspase‐3, cleaved‐PARP, p‐PI3K, PI3K, p‐AKT, AKT, p‐mTOR as well as mTOR protein were also investigated using Western blot analysis. According to our findings, miR‐215‐5p overexpression could induce apoptosis while rendering cell cycle arrest at G1 phase and reducing the proliferation of cells. Meanwhile, miRNA‐215‐5p could negatively regulate messengerRNA and protein levels of RUNX1 in MM cells. In addition, there was a similar effect in cell proliferation and apoptosis after miR‐215‐5p mimics or siRNA‐RUNX1 transfection. miR‐215‐5p inhibition inhibited apoptosis while increased the phosphorylation levels of PI3K, AKT, and mTOR proteins, whereas, miR‐215‐5p overexpression increased cell proliferation. Therefore, miR‐215‐5p inhibited MM cell apoptosis via targeting RUNX1 and suppressing the activation of the PI3K/AKT/mTOR pathway.

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An effective drug sensitizing agent increases gefitinib treatment by down regulating PI3K/Akt/mTOR pathway and up regulating autophagy in non-small cell lung cancer

Cited by 28 publications

References 48 publications

Study on the mechanisms of compound Kushen injection for the treatment of gastric cancer based on network pharmacology

Study on the mechanisms of compound Kushen injection for the treatment of gastric cancer based on network pharmacology

Integrated bioinformatics analysis to decipher molecular mechanism of compound Kushen injection for esophageal cancer by combining WGCNA with network pharmacology

miR‐215‐5p is an anticancer gene in multiple myeloma by targeting RUNX1 and deactivating the PI3K/AKT/mTOR pathway

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