Inhibitory Effects Of Rosiglitazone Combined With Cisplatin On A549 Cell Line Xenograft In Nude Mice

Objective To investigate the effect of the ligand of peroxisome proliferator–activated Receptor gamma (PPARγ) agonist Rosiglitazone (ROZ) combination with cisplatin(DDP)on growth of A549 cell line xenograft in nude mice and its mechanism.Methods The human lung cancer xenograft mode in nude mice was established A549 cell.Twenty eight Balb/c-nu mice with lung cancer xenograft were randomly divided into seven groups:①control group(NS 0.2ml);②DDP 1mg/kg group;③DDP 4mg/kg group;④ROZ 10mg/kg group ;⑤ROZ 30mg/kg group;⑥ROZ 10mg/kg+DDP 1mg/kg group;⑦ROZ 30mg/kg+DDP 1mg/kg group,all groups was given by intraperitoneal injection for eight times(one time every two days),Different treatments were served after ten days.The lenghth and width of the xenograft were measured by vernier calipers at every four days during the therapy time.The volume of the xenograft was calculated,using the standard formula,and xenograft growth curves were ploted out.The weight of primary subcutaneous xenograft and the inhibitory rate of weight of xenograft were examined at 48h after the last injection after all mice sacrificed.Jin's formula was used for estimating the efficacy of ROZ combination with DDP on the treatment of human lung cancer.Executed subcutaneous xenograft were fabricated into paraffin wax slices in order to observe the pathology form of xenograft under microscop.Immunohistochemistry staining was used for detected the expression of PPARγ,phosphatase and tensin homology deleted on chromosome ten(PTEN), Phosphorylation Serine-threonine kinase (pAkt) and cysteinyl aspartate-specific protease 3(caspase-3) of the human lung cancer xenograft mode in nude mic. Results (1)In every treatment group xenograft growth was suppressed significantly. 30mg/kg ROZ plus 1mg/kg DDP group showed significant enhancement efficacy in anti-tumor growth.(2)The weight of xenograft were respectively 283.98±35.37mg , 197.70±88.69mg , 96.50±19.76mg , 175.02±5.37mg ,142.83±44.54mg,135.70±25.27mg,45.70±9.65mg, Intraperitoneal injection of DDP 1mg/kg group,DDP 4mg/kg group,ROZ 10mg/kg group,ROZ 30mg/kg group,ROZ 10mg/kg+DDP 1mg/kg group,ROZ 30mg/kg+DDP 1mg/kg group resulted in a significant inhibition of the growth of A549 cells in vivo compared with control group(p<0.01).The inhibitory rate of weight of subcutaneous xenograft wer respectively 30.28%,65.85%,38.38%,49.65%,52.11% and 83.80%.(3) The anti-tumor effect of DDP plus ROZ was significantly enhanced compared with 1mg/kg DDP group (p<0.05) (q=0.91,1.29). (4)Immunohistochemistry staining data showed that expression of PPARγ, PTEN and caspase-3 increased in every ROZ-treatment group ,however, expression of pAkt decreased in every ROZ-treatment group .The difference was significant compared with control group.This difference of DDP plus ROZ was significantly enhanced compared with control group.(5) Adverse reaction: the weight of 4mg/kg DDP group is lower than before using of the medicine and showed the significantly(p<0.01),the other groups was not adversereaction.Conclution (1) ROZ can significantly inhibit the growth of human lung cancer xenograft mode in nude mice.(2) DDP combined with ROZ can significantly inhibit the growth of human lung cancer xenograft mode in nude mice,can produce synergetic effect.(3) The mechanism of the action of growth inhibition and chemosenitization of DDP and ROZ are associated with the activation of PPARγ, up-regulation of the PTEN,caspase-3 and down-regulation of the pAkt .