The Anti-hepatoma Effect And Molecular Mechanism Of NT157 And Cardiac Glycoside 10-4-4

As one of the serious threats to human health,hepatoma is one of the main reasons that the cure rate can hardly reach the ideal expectation:the method for treating cancer is single;after long-term use of the drug,the tumor has obvious drug resistance.This dissertation uses different methods to study the anti-tumor mechanisms of two small molecule compounds with anti-tumor effects:NT157 and cardiac glycoside 10-4-4,and to discover new anticancer drugs,research drug anti-tumor mechanisms,and even development.New drugs and treatment of cancer are of great significance.The first chapter studies the molecular mechanism of anti-liver cancer in NT157.Liver cancer is a kind of malignant tumor with a high incidence in China.Many physiological or environmental factors may induce liver cancer.Therefore,it is particularly important to identify the target and mechanism for the treatment of liver cancer drugs.NT157 is a small molecule tyrosine phosphorylation inhibitorhas a strong inhibitory effect on various cancer cells(colon cancer,prostate cancer,etc.)at the cellular level.Our experiments found that NT157 also has a strong pro-apoptotic effect in hepatoma cells,but the mechanism of action of NT157 in hepatoma cells has not been studied.We use proteomics techniques to explore the mechanism of NT157 inhibiting the growth of hepatoma cells or inducing cancer cell apoptosis at the protein level.Quantitative proteomics techniques using stable amino acid labeling with amino acids in cell culture(SILAC)were used to study the protein changes induced by NT157 in hepatoma cells.The results showed that there were 5273 proteins in the induction of apoptosis of hepatoma cells by NT157.Through the classification of these proteins,we discover the new mechanism of NT157 in hepatoma cells,which can be used for the multi-target antitumor drugs.The second chapter studies the antihepatoma effect of cardiac glycoside 10-4-4 targeted nuclear receptor Nur77.Traditional cardiac glycosides are mainly used for the treatment of various cardiac diseases including arrhythmia and chronic cardiac insufficiency.In recent years,the inhibitory effect of cardiac glycoside on cardiac glycosides has gradually been discovered and attracted the attention of pharmacologists.However,traditional cardiac glycosides are more toxic and have many adverse reactions,which are not suitable for the treatment of clinical cancer.The main reason for these adverse reactions is that the molecular mechanism of cardiac glycosides has not yet been fully understood.We have previously screened a series of cardiac glycoside derivatives and found that compound 10-4-4 has a strong anti-tumor effect.Studies on 10-4-4 have found that it can induce the expression of nuclear receptor Nur77 protein,which depends on the expression of Nur77 to induce tumor cell apoptosis and inhibit cell cycle.The exploration of the molecular mechanism of cardiac glycosides can guide the research and development of this series of drugs in the later development process,improve the efficacy,and reduce side effects.