川芎嗪联合顺铂对Lewis肺癌中Arresten和整合素α1β1及VEGF表达的影响

摘要

Objective To investigate the inhibition mechanism of tetramethylpyrazine combined with cisplatin on angiogenesis in Lewis lung cancer mice and to observe the mechanism of Arresten on angiogenesis in lung cancer. Methods The model of Lewis lung adenocarcinoma mouse xenograft was established in this work, and 40 mice were randomly divided into 4 groups: 0.9% sodium chloride solution group(NS group), tetramethylpyrazine group(TMP group), cisplatin group(DDP group), tetramethylpyrazine plus cisplatin group(TMP + DDP group), 10 mice in each group.Mice in NS group were given 0.2 mL of 0.9% sodium chloride solution, mice in DDP group were given 0.2 mL of 2 mg.kg-1 of cisplatin, mice in TMP group were given 0.2 mL of 100 mg.kg-1 of tetramethylpyrazine, mice in TMP+DDP group were given 2 mg.kg-1 of cisplatin and 100 mg.kg-1 of tetramethylpyrazine, each 0.1 mL .Tumor size was measured every day to calculate the tumor volume.The mice were sacrificed to stripp the subcutaneous tumor after continuous medication. The expressions of Arresten, integrin α1β1 and VEGF were determinated by immunhistochemistry and Western blotting. Results The tumor growth of NS group was the fastest and TMP+DDP group was the slowest. Compared with NS group, the expression of Arresten in the other three groups was increased( P<0.01) , and the TMP+DDP group exhibited the highest expression;at the same time, integrin α1β1 , VEGF in the other three groups was decreased(P<0.01), and the TMP+DDP group exhibited the lowest expression.The expression of integrinα1β1 and VEGF was negatively related to Arresten, and the expression of integrin α1β1 was positively correlated with VEGF. Conclusion TMP can inhibited the growth of Lewis lung carcinoma and angiogenesis. Moreover, in combination with cisplatin, TMP can also improved the effect of chemotherapy and then the survival state of mice. The mechanism of action, which TMP suppress tumor angiogenesis may be through improving Arresten and inhibiting integrin α1β1 and VEGF. And the action mechanism of Arresten may be implemented by inhibiting the expression of VEGF by incorporation with integrinα1β1 or by itself to inhibit the expression of VEGF.%目的：探讨川芎嗪联合顺铂抑制Lewis肺腺癌血管生成及Arresten抑制肺癌血管生成的机制。方法建立小鼠Lewis肺癌移植瘤模型,40只小鼠按随机数字表法分为4组：0.9％氯化钠溶液组( NS组)、川芎嗪组( TMP组)、顺铂组(DDP组)、川芎嗪联合顺铂组(TMP＋DDP组),每组10只。 NS组：给予0.9％氯化钠溶液0.2 mL； DDP组：给予顺铂2 mg.kg－1,0.2 mL；TMP组：给予川芎嗪100 mg.kg－1,0.2 mL；TMP＋DDP组：剂量同上,共0.2 mL。每日测量瘤体长短径并计算肿瘤体积。采用免疫组化、Western blotting法检测小鼠肿瘤组织中Arresten、整合素α1β1、血管内皮生长因子( VEGF)的表达。结果 NS组肿瘤生长最快,TMP＋DDP组肿瘤生长最慢。与NS组比较,其他3组Arresten表达量明显升高(P<0.01),TMP＋DDP组最高；其他3组整合素α1β1、VEGF表达量明显降低(P<0.01),TMP＋DDP组最低。 Arresten与整合素α1β1、VEGF表达呈负相关；整合素α1β1与VEGF呈正相关。结论川芎嗪能够抑制Lewis肺癌移植瘤生长,抑制其血管生成,与顺铂联合可提高化疗效果并改善小鼠生存状态,其作用机制可能是通过促进Arresten,抑制整合素α1β1、VEGF表达抑制肿瘤血管生成。 Arresten的作用机制可能是通过与整合素α1β1结合抑制VEGF表达或直接抑制VEGF表达抑制肿瘤血管生成。