塞来昔布联合HMG-CoA还原酶抑制剂对人肝癌裸鼠皮下移植瘤生长的影响

COMBINED INHIBITORY EFFECTS OF CELECOXIB AND HMG-COA REDUCTASE INHIBITOR ON THE GROWTH OF HUMAN HEPATOCELLAR CARCINOMA CELLS IN A XENOGRAFT MODEL

目的探讨选择性环氧化酶-2(Cyclooxygenase-2,COX-2)抑制剂塞来昔布(celecoxib)联合HMG-CoA还原酶抑制剂氟伐他汀(fluvastatin)对实验性人肝癌裸鼠皮下移植瘤生长的影响。方法接种BEL-7402肝癌细胞株的裸鼠,分别予以塞来昔布,氟伐他汀及联合用药,并对肿瘤生长进行评估。ki67免疫组化染色检测肿瘤细胞增殖,TUNEL法检测凋亡,免疫蛋白印迹法(Western blot)检测Akt、磷酸化Akt(p-Akt)蛋白的表达。结果联合应用塞来昔布及氟伐他汀明显抑制肿瘤生长,其机制可能与抑制肿瘤细胞增殖、诱导凋亡以及抑制Akt磷酸化有关。结论本研究表明塞来昔布及氟伐他汀联合用药可能更有效地治疗肝癌,为进一步防治肝癌提供了新的方法。

Objective To evaluate the effects of celecoxib（a selective COX-2 inhibitor）alone and in combination with fluvastatin（a HMG-CoA reductase inhibitor）on the growth of hepatocellular carcinoma xenograft in athymic nude mice.Methods Nude mice implanted with hepatocellular carcinoma BEL-7402 cells were given celecoxib and fluvastatin,alone and in combination,and their effect on tumor growth was evaluated.Tumor cell proliferation was analyzed by Ki-67 immunostaining and Apoptosis by TUNEL assay.Levels of phosphorylated（p-Akt）and total Akt was determined by Western blot analysis.Results In vivo,combination treatment with celecoxib and fluvastatin resulted in enhanced tumor growth inhibition,inhibition of tumor cell proliferation and apoptosis induction compared with results of single-agent treatment.Our results further demonstrated that the combinational effects of celecoxib/fluvastatin were associated with decreased levels of phospho-Akt.Conclusion These results suggest that the combination of celecoxib and fluvastatin would be more efficacious for the treatment of HCC than either treatment alone.The present study may be important in future exploration of the potential application of the combined approach in the treatment of Hepatocellular carcinoma.