选择性环氧合酶-2抑制剂NS398对人肺癌裸鼠移植瘤生长抑制作用研究

Study of a Selective Cyclooxygenase-2 Inhibitor NS398 in Suppressing the Growth of Human Lung Tumor Xenografts in Nude Mice

目的探讨选择性环氧合酶-2抑制剂NS398对人肺癌裸鼠移植瘤的生长抑制作用及其机制。方法建立人肺癌A549细胞的裸鼠皮下移植瘤模型,成瘤后20只裸鼠随机分为4组:对照组、NS398低剂量(1.5mg/kg)组、NS398中剂量(3.0mg/kg)组和NS398高剂量(4.5mg/kg)组。各组均采用腹腔注射给药,每周3次,共4周。给药期间每隔7日测量肿瘤体积。最后一次给药次日,处死裸鼠完整剥取肿瘤,测量肿瘤重量并计算抑瘤率。TUNEL法检测各组移植瘤标本细胞凋亡情况,免疫印迹法检测survivin、XIAP和cleaved caspase-3蛋白表达情况。结果 NS398各剂量组肺癌移植瘤生长速度均慢于对照组,各剂量组肿瘤重量显著低于对照组(P<0.01,P=0.000),呈剂量依赖性。各剂量组的抑瘤率分别为30.18%、46.50%和53.87%。TUNEL法结果显示,与对照组比较,NS398各剂量组凋亡指数均显著增加(P<0.01,P=0.000),并呈剂量依赖性。免疫印迹法结果显示,与对照组比较,NS398各剂量组survivin和XIAP蛋白表达量均显著减少,cleaved caspase-3蛋白表达量均显著增加(P=0.000),也呈明显剂量依赖性。结论 NS398能明显抑制人肺癌裸鼠移植瘤的生长,并诱导肿瘤细胞凋亡,其机制可能与下调survivin和XIAP蛋白表达,上调cleaved caspase-3蛋白表达有关。

Objective To investigate the inhibitory effect and mechanism of a selective cyclooxygenase - 2 inhibitor NS398 in sup- pressing the growth of human lung tumor xenografts in nude mice. Methods A human lung tumor xenografts model was established by subcutaneously injecting human lung tumor A549 cell into nude mice. Twenty nude mice was randomly assigned into four groups： control, low - dose NS398 injection（ 1.5mg/kg）, middle - dose NS398 injection（3.0mg/kg） and high - dose NS398 injection（4.5mg/kg）. Mice in every groups were treated with corresponding dosage intraperitoneally for 3 times in each week and it lasted for 4 weeks. The volume of tumor was measured in every week, the nude mice were sacrificed for quantifying the rate of tumor inhibition and the tumor was removed for calculating tumor weight in the next day of last injection. The Apoptotic cells in tumor xenografts were detected by TUNEL method, and the expression levels of survivin, XIAP and cleaved easpase - 3 were quantified by Western blot. Results The growth rate of tumor xeno- grafts in NS398 injection groups with different dosages was slower than that in control group. The tumor weight in NS398 injection groups with different dosages all significantly decreased when compared with control group（ P 〈 0.01, P---0. 000）. It showed a dose -dependent manner. The rates of tumor inhibition in NS398 injection groups were 30.18% , 46.50% and 53.87% , respectively. It showed that the apoptotic index of NS398 injection groups with different dosages was obviously increased in a dose - dependent manner when compared with control group by TUNEL detection （P 〈 0.01, P = 0. 000）. Western blot showed that the expression levels of survivin and XIAP were significantly decreased when compared with control group, however, the expression level of cleaved caspase - 3 was distinctly elevated when compared with control group. It also was a dose - dependent manner（P = 0. 000）. Conclusion The growth of human lung tumor xenografts was inhibited and apoptosis in tumor tissue was induced by NS398, which might be associated with decreased the expression of survivin and XIAP and increased the expression of cleaved caspase - 3.