Study On The Effect And Mechanism Of Novel PI3K Small Molecular Inhibitors Against Pancreatic Cancer

Objective To observe the effect of novel PI3K small molecular inhibitor BYL-93 on human pancreatic cancer cell lines CFPAC-1 and Capan-2,and to verify the anti-pancreatic cancer activity of BYL-93 from the cell level.To provide experimental basis for the development of PI3K inhibitors,but also to provide a scientific basis for the development of novel small molecular targeted therapeutic drugs.Methods CFPAC-1 and Capan-2 cells were cultured,and cell proliferation was detected by CCK-8 method;DAPI was stained to observe the nucleus;Flow cytometry was used to detect apoptosis and its cycle;Mitochondrial transmembrane potential was detected by JC-1 method;Detection of the protein expression and phosphorylation of PI3K-AKT signaling pathway by Western blot method.CFPAC-1 cells were operated by scratch test and Transwellchamber invitro invasion assay,E-cadherin and Snail gene transcription levels were detected by real time fluorescence quantitative PCR method.Results BYL-93 inhibited the proliferation of CFPAC-1 and Capan-2,and IC50 values for CFPAC-1 and Capan-2 at 24 and 48 hours were 22.7 pM,5.3 ?M and 9.0?M,2.4 ?M;5,10 and 20?M BYL-93 could induce CFPAC-1 cell apoptosis,2.5,5,10?M BYL-93 could induce apoptosis of Capan-2 cells;CFPAC-1 and Capan-2 significantly blocked the G1 phase of cells by the effects of different concentrations of BYL-93;BYL-93 showed a significant decrease in mitochondrial membrane potential on both CFPAC-1 and Capan-2 cells(P<0.001);After BYL-93 acted on CFPAC-1 and Capan-2,AKT,mTOR,70S6,S6 protein phosphorylation levels decreased,PARP split,and the effects of BYL-93 on CFPAC-1 cells were slightly stronger;With the increase of BYL-93 concentration,the migration ability of CFPAC-1 cells decreased gradually,which was concentration gradient dependent;BYL-93 can significantly inhibit the invasion and metastasis of pancreatic cancer cells,up-regulate the expression of E-cadherin mRNA,down-regulate the expression of Snail mRNA.Conclusion BYL-93 could inhibit the proliferation and metastasis of CFPAC-1 and Capan-2 tumor cells,and verify the anti-pancreatic cancer activity of BYL-93.