The Study On The Anti-tumor Activity And Mechanism Of SLL-1A-16 In Lung Cancer Cells

Lung cancer is a heterogeneous,complex and challenging disease,and it is currently the world's leading morbidity and mortality.With the industrialization,urbanization and environmental pollution around the world,the cause of lung cancer has become more complicated.Lung cancer is divided into small cell lung cancer and non-small cell lung cancer,of which non-small cell lung cancer takes part in 80-85%.The treatment of lung cancer includes surgery and radiotherapy and chemotherapy,but there are few existing chemotherapy drugs,which cause irreversible damage to patients.Therefore,it is urgent to develop a new anti-lung cancer drug with high efficacy and small side effects.Selenium cyanonicotinic acid SLL-1A-16 is a new organic selenium small molecule compound.This study first explored the inhibitory effect of compound SLL-1A-16 on the proliferation of various tumor cells,and found that SLL-1A-16 obviously inhibit proliferation of lung cancer cells.Therefore,lung cancer cells were the main research object to explore the anti-tumor activity and mechanism of SLL-1A-16 in lung cancer.First,the effect of compound SLL-1A-16 on the proliferation of lung cancer cells A549 and NCI-H460 cells,gastric cancer cells BGC-823 and MKN-28,liver cancer cells HEPG2 and'HEP3B,breast cancer cells MBA-MD-231 and MCF7,prostate cancer cells LNCAP and PC-3,colorectal cancer Caco2 and SW480 cell was detected by MTT assay.We found that SLL-1A-16 inhibited the proliferation of lung cancer cells most significantly.Then,we further studied the changes of cell cycle and apoptosis of A549 and NC1-H460 cells after treatment with compound SLL-1 A-16,Western Blot was used to detect changes in the expression levels of lung cancer-related proteins;the molecular docking method was used to simulate the possible target of compound SLL-1 A-16 to explore the molecular mechanism of inhibiting the proliferation of lung cancer cells.The results are as follows:1.MTT assay was used to detect cell viability.SLL-1A-16 was selected to treat 12 kinds of cells of 6 cancer lines.It was found that compound SLL-1A-16 significantly inhibited the proliferation of lung cancer cells,and CKK8 method was used to detect IC50 of SLL-1A-16 on lung cancer cells.The IC50 values of A549 and NCI-H460 were 20.935?M and 11.624?M,respectively.The colony formation assay showed that SLL-1 A-16 could significantly inhibit the clonality of lung cancer cells.2.Compound SLL-1A-16 blocks A549 cells in G1 phase,reduces the protein expression of Cyclin D and CDK4 in G1 phase,and has no significant cell block effect on NCI-H460 cells,but can reduce the expression of the G1 phase related protein Cyclin D.3.Compound SLL-1A-16 significantly induced apoptosis,and the apoptosis was more obvious with the increase of treatment concentration.The expression of apoptosis-related protein Bax was increased in two lung cancer cells A549 and NCI-H460,inhibition of apoptosis protein BCL2 expression was decreased while apoptosis effector protein active caspase3 expression was increased.4.Compound SLL-1A-16 up-regulates the expression of tumor suppressor factor DKK3 and phosphorylated JNK in two lung cancer cells,down-regulates the expression of phosphorylated STAT3 protein,inhibits the activation of mTOR signaling pathway and inhibits the proliferation of lung cancer cells.5.Computer molecular docking revealed that the compound SLL-1A-16 interacts with the mTOR protein and there is a possible conformation of 9 in which the compound binds to the FAT or kinase domain of the mTOR protein,indicating SLL-1 A-16 is capable of targeting the mTOR signaling pathway and inhibiting its activation.The above results indicate that the compound SLL-1A-16 can down-regulate the expression of p-STAT protein,up-regulating the expression of tumor suppressor factor DKK3,activate JNK to promote apoptosis and inhibit the activation of mTOR-related signaling pathway in lung cancer cells,thereby inhibiting cell proliferation.Compound SLL-1A-16 may be used as a new small molecule drug in targeted therapy for lung cancer in the future.