Anti-tumor Mechanism Of Benzoxaine,N-substituted Benzylidene Pyrrolidine Diketone And Indole Amide Compounds

Rapid proliferation of tumors depends on the generation of neovascularization.Neonatal blood vessels can provide sufficient oxygen and nutrition for the rapid proliferation of tumors and can take metabolites to provide a good growth microenvironment for the tumor.Currently available anti-vascular drugs are sorafenib,sunitinib and so on,although these drugs in the clinical to obtain a certain therapeutic effect,but the resistance and side effects of the production limit their clinical application,therefore,The urgent need to develop a new type of highly effective tyrosine kinase inhibitors,effectively hinder tumor angiogenesis.This study was to investigate the antitumor mechanisms of ZD-21,XCF-37b and ZJQ-24,which have been screened for anti-vasoactive compounds.ZD-21 has a certain anti-angiogenic activity,so we explore the anti-angiogenesis mechanism of ZD-21.We found that 2.5μM of ZD-21 can inhibit endothelial cell tubule formation and cell migration.20μM of ZD-21 treated HUVEC cells 2h,can inhibit the phosphorylation of VEGFR2,it also can inhibiting the downstream of the VEGFR2 signal pathway,such as p-Erk,p-FAK expression activation.Detection of ZD-21 cytotoxicity on tumor cells found that ZD-21 was more sensitive to HepG2 cells with an IC50 of 5.042 ± 0.776 μM.5μM ZD-21 treatment HepG2 cells 48h,the cell emerge G1 arrest,cell apoptosis rate is 40%.The apoptotic protein PARP and Caspase-3 were cut after treatment with 5μM ZD-21 for 48 h,and is concentration dependent.Previous studies have shown that XCF-37b has a good anti-angiogenic activity in vitro,in order to explore its in vivo anti-angiogenic activity.We used the matrix glue model to study the activity of XCF-37b to inhibit the subcutaneous capillary angiogenesis in mice.It was found that the matrix of containing 20,40,60 mg/kg XCF-37b could not see red blood cells,shows XCF-37b can inhibit the growth of mouse capillaries.The expression of HIF-la and VEGF in the cells treated with 10μM XCF-37b for 24h was significantly lower than that of the control group(P<0.05).The levels of HIF-1α and VEGF in the cells were significantly lower than those in the control group.The expression of matrix metalloproteinases(MMPs)in the process of tumor metastasis and angiogenesis was inhibited by 10μM XCF-37b treatment.The expression of MMP-9 in HT-29 cells was decreased secreted MMPs activity,10μM XCF-3 7b can reduce HT-29 cells secreted MMPs activity,and a certain concentration-dependent.Because of the good anti-angiogenesis activity of XCF-37b in vitro,we used HT-29 cells to construct mouse xenograft tumor model to detect the anti-angiogenic and anti-tumor activity in vivo,and the mouse were treated with 20mg/kg,40mg/Kg,60mg/kg consecutive administration for 7 days,we found that 60mg/kg of XCF-37b has a certain ability to inhibit tumor growth,tumor inhibition rate is 50%.The positive rate of CD-31 was inhibited by 64.9%in the 60mg/kg XCF-37b group,and the positive rate of Ki-67 was inhibited 57.3%,and the apoptosis rate is 85%.This suggests that compound XCF-37b can inhibit tumor growth by reducing tumor angiogenesis,inhibiting tumor cell proliferation,and inducing cell apoptosis.The results showed that ZJQ-24 could inhibit the activity of PI3K/AKT/mTOR signaling pathway in HepG2 cells.The results showed that ZJQ-24 could inhibit the activation of PI3K/AKT/mTOR signaling pathway in HepG2 cells.In this study,we used HepG2 cells to construct the model of xenografts in mice.The rats were treated with 20mg/kg,40mg/kg and 60mg/kg for 14 days.The results showed that 40mg/kg and 60mg/kg of ZJQ-24 can inhibit the growth of tumor in mice,tumor inhibition rate is 72.6%.Immunohistochemical study showed that the cell proliferation of the two groups of tumor cells Ki-67,mRNA translation-related protein p-4EBP1 and p-mTOR,p-AKT,p-S6,Rictor,Raptor and other mTOR signal pathway protein factor The expression also has a significant downgrade phenomenon.In conclusion,The compound ZD-21 had a certain inhibitory effect on the proliferation,migration and microtubule formation of HUVEC cells.The compound XCF-37b had good in vitro and in vivo anti-angiogenic activity in vitro.Compound ZJQ-24 had some inhibitory effects on tumor growth.