塞来昔布联合卡培他滨对H_(22)肝癌移植瘤小鼠的抑制作用及机制

Inhibitory Effects of Celecoxib Combined with Capecitabine on H22 Hepatoma Mice and Its Mechanism

目的探讨塞来昔布联合卡培他滨对H22肝癌移植瘤小鼠的抑瘤作用及作用机制。方法 BALB/c裸鼠皮下接种H22肝癌细胞,建立移植瘤模型。40只模型小鼠随机分为对照组、塞来昔布组(100mg/kg)、卡培他滨组(755mg/kg)和联合干预组(100mg/kg塞来昔布+755mg/kg卡培他滨)4组,每组10只。接种后第3天起,每天灌胃给药1次,对照组给予等量生理盐水,连续15d。处死动物,剥离完整瘤组织,称重并计算抑瘤率。采用荧光定量PCR和Western blotting检测瘤组织中核转录因子kappaB(NF-κB)p65和环氧合酶(COX)-2的mRNA及蛋白表达。结果塞来昔布和卡培他滨组抑瘤率分别为30.2%和49.9%,而联合干预组抑瘤率为75.4%,显著高于单药组(P<0.01,P<0.05)。荧光定量PCR结果显示,塞来昔布和联合干预组COX-2的mRNA表达显著低于对照组(P<0.001),但对NF-κBp65的mRNA表达无明显影响。卡培他滨对NF-κBp65和COX-2的mRNA均无明显影响。Western boltting结果显示,塞来昔布和联合干预组小鼠瘤组织中NF-κBp65和COX-2的蛋白表达水平均显著低于对照组(P<0.05),卡培他滨组与对照组相比差异无统计学意义(P>0.05)。结论塞来昔布可通过抑制H22肝癌移植瘤小鼠瘤组织中NF-κBp65和COX-2的表达发挥抗肿瘤作用,且与卡培他滨联合应用具有协同增效作用。

Objective To evaluate the inhibitory effect and its mechanism of celecoxib combined with capecitabine on the growth of implanted H22 hepatoma in mice. Methods Tumor model was established by hypo- dermical injection of H22 ceils in BALB/c nude mice. Forty mice were equally randomly divided into 4 groups： control group, celecoxib group （receiving 100 mg/kg celecoxib）, capecitabine group （receiving 755 mg/kg capecitabine）, and combined treatment group （receiving 100 mg/kg of celecoxib and 755 mg/kg of capecit- abine） . From the third post-implantation day, each mouse was given relevant drug （or normal saline） by oral gavage. Fifteen days later, all mice were sacrificed and the tumor tissues were measured. The mRNA and protein levels of nuclear factor kappa-B （NF-KB） p65 and cyclooxygenase （COX） -2 in tumor tissues were detected bythe quantitative polymerase chain reaction （qPCR） and Western blotting, respectively. Results The tumor in- hibition rate was 30. 2% in celecoxib group and 49. 9% in capecitabine group, which was significantly lower than that （75.4%） in the combined treatment group （P 〈0. 01, P 〈0. 05, respectively） . qPCR showed a significant decrease of the mRNA expression of COX-2 in celecoxib group and combined treatment group when compared with control group （P 〈0. 001 ） , but no significant change in NF-KB p65. Capecitabine had no signifi- cant effects on the mRNA expression of COX-2 and NF-KB p65. Western blotting showed that celecoxib and com- bined treatment significantly inhibited the protein expression of COX-2 and NF-KB p65 （ P 〈 0. 05 ）, but not capecitabine. Conclusion Celecoxib can enhance the antitumor effect of capecitabine by inhibiting the expres- sions of COX-2 and NF-KB p65 in mice bearing Hzz implanted tumor.