The Anti-proliferation Of Nedaplatin Combined With ABT-737 In Solid Tumor Cells And Its Mechanism

Objective Nedaplatin is a second-generation platinum complex,based on its pronounced anti-cancer activities against several solid tumors.The anti-cancer activity of Nedaplatin is equivalent to that of cisplatin,but with lower nephrotoxicity and gastrointestinal toxicities.ABT-737 is a novel small molecule inhibitor of Bcl-2 family proteins,which can inhibit the activity of Bcl-2,Bcl-xL and Bcl-w,and then induce apoptosis in tumor cells.However,over-expression of Mcl-1 often induced the resistance to ABT-737 in several solid tumors.In this context,the present study aimed to investigate the potential anti-cancer effect by combining nedaplatin with ABT-737 and explore its mechanism,thereby provide theoretical basis and experimental data for Nadaplatin and ABT-737 in clinical solid tumors therapy.Methods ?SRB assay and colony formation assay were used to detect the anti-proliferation of nedaplatin combined with ABT-737 on human solid tumors cells.?We analyzed apoptosis by propidium iodide staining.?We determined mitochodria membrane potential by JC-1 staining.?Western blot was used to detect the expression of related proteins.?We analyzed mRNA level by Real-Time RT PCR.?The over-expression of the target protein was amplified by plasmid transfection.Results ?Nedaplatin plus ABT-737 synergistically inhibited the proliferation of human solid tumor cells.? Nedaplatin plus ABT-737 synergistically inhibited the colon formation of A549 cells.?Nedaplatin plus ABT-737 synergistically induced apoptosis both in A549 and 95-D cells.?The apoptosis induced by nedaplatin plus ABT-737 was through mitochondrial pathway.?Nedaplatin plus ABT-737 inhibited the expression of XIAP and Mcl-1,thus activated Caspase-3 and PARP,and finally induced apoptosis in solid tumor cells.?Nedaplatin plus ABT-737 was unable to inhibit the expression of Mcl-1 protein by transcriptional level.?Synergistic effect of nedaplatin combined with ABT-737 could promote the degradation of Mcl-1.?Overexpression of Mcl-1 rescued cancer cells from synergistic killing by nedaplatin plus ABT-737.Conclusion The combination of nedaplatin and ABT-737 showed synergistic anti-solid tumor effect by promoting the degradation of Mcl-1,activating Caspase-3 and cleave PARP and inducing apoptosis in solid tumor cells.