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Objective To investigate the effect of MDM2 inhibitor RG-7388 on the proliferation, cell cycle, and apoptosis of diffuse large B-lymphoma (DLBCL) cells. Methods DLBCL cell strains SUDHL2 and HBL1 were treated with 2, 4, and 8 μmol/LRG7388, respectively. Cell proliferation was detected by CCK8 and EdU methods. Apoptosis was measured by Annexin V–FITC/PI double staining and Caspase 3/7-Glo enzyme activity methods. Cell cycle was assessed by flow cytometry. Changes in the expression of cell cycle and apoptosis-related proteins were determined by Western blot. Results The IC50 of RG7388 for inhibiting SUDHL2 and HBL1 cells were 3.36 and 3.76 μmol/L, respectively, and the inhibitory effect of RG7388 was dose dependent. The proportions of G1 phase and apoptotic cells in the SUDHL2 and HBL1 cells treated with different doses of RG7388 were significantly higher than those in the control group (all P<0.05). The activity of Caspase 3/7 increased gradually with RG7388 concentration, compared with that in the control group. The expression levels of p53, p27, p21, and PARP increased, whereas the expression of Mcl-1 and Bcl-xL was down-regulated (all P<0.05). Conclusion MDM2 inhibitor RG-7388 inhibits the proliferation of DLBCL cells, triggers cell cycle arrest in the G1 phase, and induces apoptosis through the p53 pathway.
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Objective To find novel lead compounds as p53-MDM2 inhibitors by drug repurposing strategy. Methods The p53-MDM2 inhibitory activities of compounds were determined by FP and western blotting. MTT method was used to determine the in-vitro antitumor activities. The metabolites in human liver microsomes were tested. Results Bepridil showed excellent in-vitro anti-tumor activity and strong p53-MDM2 protein binding inhibitory activity, which can significantly reduce the expression of MDM2 protein in a dose-dependent manner. The metabolites in human liver microsomes are mainly benzene ring hydroxyl mono-oxidation metabolites. Conclusion Bepridil can be used as a lead compound for p53-MDM2 protein binding small molecule inhibitors for subsequent structural optimization design studies.
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The discovery of the key negative regulator MDM2 and the detailed mechanism of MDM2-P53 protein-protein interaction provide a great opportunity to activate P53 by inhibiting MDM2-P53 interaction with MDM2 inhibitor.In this article,the author will review the accomplishment in the area of MDM2 inhibitor treatment on tumors of urological system.The detailed mechanism and the signal pathways involved are summarized simultaneously.