Gefitinib对激素非依赖性前列腺癌的治疗及其效应初探

Inhibitory effect of Gefitinib on hormone independent prostate cancer in vitro and in vivo

目的探讨受体酪氨酸激酶抑制剂Gefitinib在体内外对激素非依赖前列腺癌(HIPC)的抑制作用及其效应机制。方法不同浓度的Gefitinib处理HIPC细胞株PC-3后24～120h,MTT法检测细胞生长抑制率,Westernblot检测细胞表皮生长因子受体(EGFR)、蛋白激酶B(Akt)、丝裂原活化蛋白激酶(MAPK)和蛋白激酶C(PKC)蛋白的表达水平。建立PC-3细胞裸鼠移植瘤,观察Gefitinib体内的肿瘤抑制率。结果Gefitinib抑制PC-3细胞生长呈现时间-浓度依赖性,最佳抑制浓度为5ng/mL,最佳抑制时间为72h,细胞生长抑制率稳定在50%～60%。与对照组比较,经Gefitinib处理后PC-3细胞中EGFR、Akt蛋白水平分别降低了70.44%和59.01%,而MAPK及PKC蛋白分别仅降低34.83%和33.40%。裸鼠实验结果表明,Gefitinib可显著抑制HIPC肿瘤的生长,抑制率高达53.95%,常规病理HE染色提示大片灶状癌细胞坏死。结论Gefitinib可在体内外显著抑制HIPC的生长,其机制可能为通过降低癌细胞EGFR和胞内蛋白Akt的表达水平来发挥作用。

Objective To investigate the inhibitory effect of Gefitinib in the treatment of hormone independent prostate cancer （HIPC） in vitro and in vivo. Methods The HIPC cell line PC-3 was treated with Gefitinib in different concentrations for 24-120 h,and then the cell-inhibition ratio （CIR） was measured with MTT and expression levels of proteins,such as epidermal growth factor receptor （EGFR）,protein kinase B （Akt）,mitogen aetivatedprotein kinase （MAPK） and protein kinase C （PKC） were determined by Western blot. Results The inhibitory effect of Gefitinib on PC-3 cells＇ growth showed a time-and density-dependence,and the ideal inhibitory concentration and time were 5 ng/mL and 72 h,in which the CIR of PC-3 cells was 50%-60%. Compared with the control group,expression levels of protein EGFR and Akt were significantly decreased by 70.44% and 59.01% in PC-3 cells in the Gefitinib group; expression levels of MAPK and PKC was decreased by 34.83% and 33.40%. In an in vivo experiment,compared with the control group,the growth of HIPC tumors in the Gefitinib group was significantly inhibited by 53.95%. Conclusion Gefitinib could significantly induce inhibitory effects on growth of HIPC in vitro and in vivo by down-regulation of expressions of EGFR and its intra-cellular effective proteins Akt in PC-3 cells.