In Vitro Anticancer Activity And Mechanism Of Novel Mononuclear Polypyridylruthenium (?) Complexes

Objective:To synthesize a series of novel mononuclear polypyridylruthenium?II?complexes.To screen for a highly active and low toxic candidate compound and study the mechanism of its anti-tumor action.The results will be helpful for the development of novel ruthenium complexes as potential anticancer agents with high efficiency and low toxicityMethods:In this paper,we synthesized three new mononuclear polypyridylruthenium?II?complexes and through the method of CCK-8 to test its,antitumor activity in vitro towards four cell lines?HepG2,L-02,ACHN,HEK–293?,choosing the best one to conduct the next experiments.By intracellular localization experiments,specific sites of drug accumulation in cells were photographed.The cell cycle experiment visually demonstrated whether the complexes had cell cycle arrest.In addition,we also studied the anti-tumor mechanism of ruthenium complex by cell apoptosis test,mitochondrial membrane potential detection and protein Western Blot.Results:CCK-8 results showed that Ru?dppz??bb₇?had the best in vitro activity,and its activity to HepG-2 cells was stronger than cisplatin,while its toxicity to normal hepatocytes L-02 was weaker than cisplatin.The results of intracellular localization showed that the most active complex Ru?dppz??bb₇?was mainly concentrated in the cell nucleus?including nucleolus?at low concentration,and accumulated in the mitochondria of the cell at high concentration.Cell cycle experiment results showed that Ru?dppz??bb₇?could block the cell cycle of HepG-2 cells in S phase.The results of apoptosis experiment showed that Ru?dppz??bb₇?could induce apoptosis of HepG-2 cells and have concentration dependence.The results of mitochondrial membrane potential test showed that Ru?dppz??bb₇?could decrease the mitochondrial membrane potential of HepG-2 cells.The results of Western Blotting showed that Ru?dppz??bb₇?up-regulated the expression of HepG-2 cells?H2AX,P53,Bax,Caspase-3 and Caspase-9,while down-regulated the expression of Bcl-2.Conclusion:Ru?dppz??bb₇??Ru3?has the effect of inhibiting the proliferation of HepG-2cells in liver cancer.The mechanism of its anti-tumor activity in vitro is to cause DNA damage,which leads to the activation of P53 tumor suppressor gene and further activation of Bcl-2 family protein,and induces tumor cell apoptosis through the Caspase mediated mitochondrial apoptosis pathway.