β-肾上腺素能受体阻滞剂和COX-2抑制剂在结直肠癌肝转移中的作用研究

目的: 研究β-肾上腺素能受体阻滞剂和环氧合酶-2（COX-2）抑制剂在结直肠癌肝转移过程中发挥的作用及潜在机制。方法: 本研究首先通过体外结直肠癌细胞实验，研究不同浓度的β-肾上腺素能受体阻滞剂和COX-2抑制剂对结肠癌细胞的增殖抑制作用，血管内皮生长因子（VEGF）分泌能力和活性氧（ROS）表达能力，随后于体内构建小鼠结直肠癌肝转移动物模型，对小鼠模型的肿瘤转移率、肿瘤数量、肿瘤最大重量、肿瘤最大直径和VEGF mRNA进行检测。结果: β-肾上腺素能受体阻滞剂和COX-2抑制剂对结肠癌细胞具有显著的增殖抑制作用，呈给药剂量依赖性。当β-肾上腺素能受体阻滞剂的浓度为200 μmol/L时，肿瘤细胞的增殖抑制率为(39.00±2.00)%，VEGF分泌量为(55.44±7.65) pg/mL，当COX-2抑制剂的浓度为2 μmol/L时，肿瘤细胞的增殖抑制率为(33.67±1.15)%，VEGF分泌量为(37.75±4.08) pg/mL，各组内比较差异均具有统计学意义（P<0.05）。与使用β-肾上腺素能受体阻滞剂相比，使用COX-2抑制剂明显地抑制肝脏转移瘤的生长效果，比较差异具有统计学意义（P<0.05），联合使用β-肾上腺素能受体阻滞剂和COX-2抑制剂可有效降低肿瘤的最大重量、尺寸和VEGF mRNA表达水平［（0.20±0.13） g，（1.98±0.33） mm和0.22±0.06］，与对照组相比［（0.88±0.13） g，（5.45±0.88） mm和1.03±0.14］，与β-肾上腺素能受体阻滞剂组［（0.50±0.16） g，（3.45±0.45） mm和0.75±0.08］和COX-2抑制剂组［（0.34±0.09） g，（2.73±0.24） mm和0.50±0.08］相比，差异均具有统计学意义（P<0.05）。结论: 在结直肠癌肝转移过程中，β-肾上腺素能受体阻滞剂和COX-2抑制剂通过调控肿瘤表达ROS，促进肿瘤细胞凋亡；通过协同作用调控肿瘤细胞VEGF分泌，抑制肿瘤细胞新生血管形成和迁移。

Effects of beta-adrenergic receptor blockers and COX-2 inhibitors on liver metastasis of colorectal cancer

AIM: To study the role and potential mechanism of β-adrenergic receptor blockers and COX-2 inhibitors in liver metastasis of colorectal cancer. METHODS: The effect of different concentrations of β-adrenoceptor blockers and COX-2 inhibitors on colon cancer cell proliferation, VEGF secretion and ROS expression were investigated by in vitro colorectal cancer cell experiments. Then, animal models of liver metastasis of colorectal cancer were performed. The tumor metastasis rate, tumor number, maximum tumor weight, maximum tumor diameter, and VEGF mRNA were measured. RESULTS:β-adrenergic receptor blockers and COX-2 inhibitors had significant proliferation-inhibitory effects on colon cancer cells in a dose-dependent manner. When the concentration of β-adrenergic receptor blocker was 200 μmol/L, the tumor cell proliferation inhibition rate was (39.00±2.00)% and the VEGF secretion was (55.44±7.65) pg/mL. And the tumor cell proliferation inhibition rate was (33.67±1.15)%, and the VEGF secretion was (37.75±4.08) pg/mL when the concentration of COX-2 inhibitor was 2 μmol/L. The difference was statistically significant in each group (P<0.05). Compared with the use of β-adrenergic receptor blockers, the use of COX-2 inhibitors significantly inhibited the growth of liver metastases, the difference was statistically significant (P<0.05).Combining β-adrenergic receptor blockers with COX-2 inhibitors could effectively reduce tumor maximal weight, size, and VEGF mRNA expression levels ［（0.20±0.13）g, （1.98±0.33）mm and 0.22±0.06］ as compared with the control group ［（0.88±0.13）g, （5.45±0.88）mm and 1.03±0.14］ and the β-adrenergic receptor blocker group ［（0.50±0.16）g,（3.45±0.45）mm and 0.75±0.08］ and the COX-2 inhibitor group ［（0.34±0.09）g, 2.73±0.24）mm and 0.50±0.08］, the difference was statistically significant (P<0.05). CONCLUSION: In the process of hepatic metastasis of colorectal cancer, β-adrenergic Receptor blocker and COX-2 inhibitors promote tumor cell apoptosis by regulating tumor expression of ROS, regulating VEGF secretion in tumor cells through synergistic action, and inhibiting neovascularization and migration of tumor cells.