| Under current medical conditions,we cannot completely eradicate malignant tumors,so drug chemotherapy plays an important role in the treatment of cancer.At present,there are few kinds of chemotherapeutic drugs used clinically,and the side effects are large,and most of the drugs are only targeted.The traditional drug development and screening process requires a large amount of time and clinical trials,which is of little significance for relieving the severe market demand for anti-tumor drugs.The use of gene chip technology to analyze gene expression profiles of malignant tumors and compare the analysis results through bioinformatics databases can accelerate the drug development process,reduce drug screening time,and save costs.The purpose of this study is to propose a new drug development and screening model,and to look for possible new,low-toxicity,high-efficiency anti-tumor drugs,providing technical support for clinical drug discovery and treatment of lung adenocarcinoma.In the process of tumor development,the body's own normal metabolic pathways will be abnormal,in which the peroxidase-activated alpha(PPAR?)receptor is closely related to the abnormal metabolism of tumor lipids,and the drugs that regulate metabolic pathways may be new antitumor drugs.This study intends to use the new method of gene expression profiling to find old drugs that have been used clinically,have clear pharmacological effects,and can regulate metabolism.The drug re-localization analysis was performed for drug candidates with small toxic side effects and significant research significance to determine their possible anti-tumor drug targets,and to determine whether they could inhibit the growth of tumor cells,laying the foundation for the possible future anti-tumor mechanisms.In the course of the study,some possible anti-lung adenocarcinoma drug candidates were initially screened through lung adenocarcinoma gene expression profiles.Based on clinical data and literature analysis,we selected bezabebat,a hypolipidemic drug with known pharmacological functions,low toxicity and side effects,and which can activate PPAR? receptor pathway to significantly regulate lipid metabolism,as the most suitable candidate for anti-lung adenocarcinoma.New pharmacological localization of anti-tumor pathways through drug relocation techniques,prediction of anti-tumor target proteins in bioinformatics databases,and prediction of anti-tumor targets of bezafibrate and PPAR? receptor proteins using computer simulation software.In vitro cell proliferation inhibition experiments also showed that bezafibrate significantly inhibited the growth of lung adenocarcinoma cells.Therefore,it is speculated that the drug targeting the PPAR? receptor pathway may be a new anti-tumor drug,and its specific anti-tumor mechanism still needs further study.The research content and achievements of this paper are as follows:(1)GSE7670 and GSE27262 were selected as the appropriate lung adenocarcinoma gene expression profile datasets using the GEO database of the NCBI of Bioinformatics.Using the bioinformatics analysis software Dchip and Array Express to standardize processing and quality analysis of the two sets of chip sample data,delete some of the sample data with large deviations and perform quality control.Using BRB-Array Tools and Venny software to construct a differentially expressed gene profile of lung adenocarcinoma,a total of 366 common differential genes were obtained,of which 93 common differential genes were up-regulated and 273 genes were down-regulated.The obtained differential gene set was analyzed by GSEA,and 14 biological signal pathways were closely related to the occurrence and development of lung adenocarcinoma.These pathways are mainly involved in cell cycle changes,cellular microenvironment changes,substance metabolism(such as abnormal lipid metabolism,peroxidase-activated receptors),and EGF signaling pathways.The differential genes obtained were introduced into the bioinformatics CMap database and some lung adenocarcinoma candidates such as heat shock 90 inhibitors,hypolipidemic agents,PPAR receptor agonists and HDAC inhibitors were obtained.(2)The pharmacological relocalization analysis of drug candidates was performed using drug relocation techniques.Drugs with greater toxicity and less significant significance were selected.The PPAR agonist bezafibrate was selected as a new candidate drug for lung adenocarcinoma.By using bioinformatics databases such as Super Target and String to predict the target protein of bezafibrate,four target proteins with significant effects were obtained,namely FABP1,CRP,PPARD,and PPARG.These genes can lead to the development of tumors,inhibit the inflammatory response,and can significantly regulate metabolic abnormalities.Computer-assisted tools were used for molecular docking simulations of bezafibrate and PPAR receptor proteins to predict potential drug targets.The successful prediction of the existence of some targets,of which the best free energy of-7.2,and local optimization of the optimal site,successfully screened nine amino acid residues and the drug bezafibrate bind tightly.Among them,the amino acid residue LYS183 is the optimal site,and there are two best forces at its site,1.872 and 1.994,respectively.(3)A preliminary experiment was conducted to study the mechanism of Benazebate's lung adenocarcinoma activity using two tumor cell in vitro inhibition experiments: A549 and H460.During the test,the logarithmic cells in good growth state were used for drug treatment.The results showed that bezafibrate significantly inhibited both lung adenocarcinoma cells,and that with the increase of time,the drug dose and inhibitory effect showed a certain degree of positive correlation.It can be speculated that bezafibrate can be used as a new anticancer drug candidate.As for the mechanism of action of its regulation of metabolic abnormalities to inhibit tumor growth,further experimental verification is needed. |
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