Study On Antitumor Effect Of Novel Dimethylamine P53-MDM2 Interaction Inhibitor And Its Underlying Mechanism

Cancer is a common disease that threatens the quality of life and health of human beings and there is no cure for it till now.Therefore,the research on new compounds with anti-cancer activity and their anti-cancer mechanism is the main direction of anti-cancer compounds research and development.p53 gene is a tumor suppressor gene closely related to human tumors.It has the functions of maintaining genome stability,inhibiting and preventing cell transformation.More than half of all human tumors are related to the mutation of p53 gene.And the function and expression of p53 gene are obviously inhibited in the remaining patients without mutation of p53 gene.MDM2 is the regulation factor of p53.It is abnormally overexpression,which suppress the tumor-inhibitory function of p53.Hence,p53-MDM2 interaction is a validated target for antitumor drug development.We screened a series of multi-component compounds with a p53-MDM2 screening cell models and found that cyz2017 had good activity of inducing p53 into the nucleus.Its anti-proliferation activity was determined using Cell Counting Kit.The inhibitory effects on p53-MDM2 interaction was validated by detecting the expression changes of p53 and MDM2 protein levels using immunoblotting and immunohistochemistry.Cell cycle and cell apoptosis were determined through flow cytometry and one-step TUNEL cell apoptosis detect kit,respectively.In the present study,the phenomena of cell aggregation induced by cyz2017 was also analyzed immunofluorescence assay and continuous photography of living cells.What’s more,the antitumor activity of the compound in vivo was determined by the establishment of HCT116 subcutaneous xenograft model.The results showed that cyz2017,a novel p53-MDM2 interaction inhibitor,had good anti-tumor pharmacological activity in vitro.It greatly suppressed theproliferation of cancer cells with wild type p53.Besides,cyz2017 can induce the increased expression of p53 and its downstream protein MDM2 and p21,which confirmed that cyz2017 can activate p53 signaling pathway.Moreover,the induction of cell cycle arrest and the promotion of tumor cells apoptosis were also verified.In animal experiments,cyz2017 also showed good antitumor activity in vivo,which can effectively inhibit tumor growth compared with the control group.Besides,preliminary studies have proved that cyz2017 compounds have aggregation effect on cancer cells.It is clear that the effect of cyz2017 compounds on promoting aggregation of cancer cells is not related to p53 protein,but may be related to colorectal cancer cells.Although the mechanism of its anti-tumor effect and promoting aggregation was preliminarily explored,it provides some cues for antitumor drug development.Further studies are needed to clarify the specific molecular mechanism underlying the pharmacological effects of cyz2017.