The Study On The Anti-lung Cancer Activity And Mechanism Of Flurbiprofen Organoselenium Compounds

As the malignant tumor with the highest mortality rate in the world,lung cancer is seriously threatening the survival and development of human society.The incidence and mortality of lung cancer are increasing year by year.Non-small cell lung cancer is one of the most common types of lung cancer.Surgical treatment,chemotherapy and radiotherapy are currently the most common treatments.This study aims to explore the effects of the new Flurbiprofen organoselenium compounds RY-1-92 and SLL-1-40 on the activity of non-small cell lung cancer cells,and the possible molecular mechanisms..1.The screening study on the inhibitory effects of RY-1-92 and SLL-1-40 on the proliferation of a variety of cancer cellsCompound RY-1-92,SLL-1-40(3,10,30,100,300μM)were used to treat A549,NCI-H460 lung cancer cells,BGC-823,MKN-28 gastric cancer cells,HEPG2,SMMC-7721 liver cancer cells,MCF-7,MDA-MB-231 breast cancer cells,SW480,Caco-2 colorectal cancer cells,and NCM460 normal intestinal epithelial cells respectively for 48 h.MTT experiment results show that both compounds can inhibit the proliferation of cancer cells,but compared with the inhibitory effect of compound SLL-1-40,compound RY-1-92 has the strongest inhibitory effect on A549 and NCI-H460 lung cancer cells.It significantly inhibits its proliferation and is less toxic to normal cells.Therefore,we further studied the effect and mechanism of RY-1-92 on the activity of A549 and NCI-H460 lung cancer cells.2.The effect of RY-1-92 on the cell cycle and apoptosis,clone formation and migration ability of A549 and NCI-H460 lung cancer cellsCompound RY-1-92(10,30μM)treated A549 and NCI-H460 lung cancer cells for 48 h.The results of flow cytometry showed that compound RY-1-92 can increase the number of cells in the G2/M phase,and promote the number of apoptotic cells of the two types of lung cancer cells.Western Blot experiments further showed that compound RY-1-92 treatment can significantly reduce the expression levels of cyclin Cyclin B1 and cyclin-dependent protein kinase CDK1,and up-regulate the expression of apoptotic protein BAX.The results of the plate clone formation experiment showed that the number of clone populations of lung cancer cells treated with compound RY-1-92 was significantly reduced.The scratch test results showed that the migration distance of lung cancer cells was shortened after treatment with compound RY-1-92.The above research results indicate that the compound RY-1-92 regulates the expression of G2/M phase-related proteins and apoptosis proteins to plays a role on cell proliferation activity and cell clone formation of lung cancer cells.3.The molecular mechanism of the inhibitory effect of RY-1-92 on non-small cell lung cancer cellThrough database mining and analysis,we found that TRPV1 may be a potential target of RY-1-92.The expression changes of TRPV1 protein and related proteins that may be its downstream targets were detected at the protein level.Western Blot results showed that the compound RY-1-92 can significantly inhibit the expression level of TRPV1 protein and its downstream protein p-ERK,p-JNK,and p-P38 associated with MAPK signaling pathway,and down-regulate the expression level of p-AKT protein.4.The inhibitory effect of RY-1-92 on tumors in mice bearing lewis lung cancerThe lewis lung cancer tumor-bearing mouse model was established by injecting Lewis lung cancer cells into the axilla of the right forelimb of C57 BL/6 mice,RY-1-92 10 mg/kg,20 mg/kg and Gemcitabine hydrochloride 25 mg/kg,were intraperitoneal injection to mice.The whole process continuoued for 15 days.The results of experiments in vivo showed that,compared with the model group,compound RY-1-92 treatment reduced the volume and weight of tumors in tumor-bearing mice,suggested RY-1-92 significantly reduced the proliferation ability of lung cancer cells in vivo.Western Blot experiments showed that compound RY-1-92 treatment can inhibit the growth of tumors in mice bearing lewis lung cancer by affecting the expression of G2/M phase-related proteins and apoptosis-related proteins.In summary,compound RY-1-92 can inhibit the proliferation of lung cancer cells in vitro and in vivo.Down-regulating the expression of TRPV1 protein,MAPK signaling pathway-related proteins and p-AKT protein involved in the uderlying mechanins of RY-1-92.Our research experiments have important clinical research significance for the further development of RY-1-92 as a new lung cancer targeted drug.