CAJ | 학술논문

目的:探讨雷帕霉素靶蛋白(mTOR)抑制剂雷帕霉索(rapamycin)与丝裂原激活蛋白激酶/细胞外信号调节激酶的激酶(MEK)抑制剂PD98059对小鼠结直肠癌的联合作用及机制.方法:将二甲基肼注射于小鼠颈后20周,建立小鼠结直肠癌模型.从第16周起给予雷帕霉素、PD98059和雷帕霉素+PD98059腹腔注射,共8周;至24周处死实验动物,测算肿瘤体积,以HE染色判断肿瘤发生率;应用免疫组化法检测肿瘤组织mTOR、p70s6K、4E-BPl蛋白的磷酸化水平.结果:雷帕霉素、PD98059及雷帕霉素+PD98059干预组小鼠结直肠癌发生率显著低于模型组(44.44%、38.89%、6.67%比77.78%,P均<0.05);肿瘤体积显著小于模型组[分别为(6.153±2.192)、(8.85±3.983)、(2.917±0.191)比(16.136±6.855)mm3,P值均<0.05];蛋白磷酸化水平显著低于模型组,mTOR蛋白磷酸化水平分别为69.584%±3.600%、72.381%±8.561%、14.430%±2.413%比91.689%±1.994%;p70s6K分别为84.315%±3.132%、81.183%±3.980%、12.135%±2.382%比91.451%±2.160%;4E-BPl分别为65.288%±4.259%、66.641%±4.296%、19.119%±6.297%比75.999%±4.417%(P均<0.05).且在降低肿瘤发生率、缩小肿瘤体积以及抑制mTOR信号通路活性方面,雷帕霉素+PD98059干预组的效果显著优于雷帕霉素及PD98059单独用药,差异有统计学意义(P均<0.05).结论:雷帕霉素与PD98059可联合抑制小鼠结直肠癌的发生和生长,其作用机制可能涉及对mTOR信号转导通路相关蛋白磷酸化水平的抑制
목적:탐토뢰파매소파단백(mTOR)억제제뢰파매색(rapamycin)여사렬원격활단백격매/세포외신호조절격매적격매(MEK)억제제PD98059대소서결직장암적연합작용급궤제.방법:장이갑기정주사우소서경후20주,건립소서결직장암모형.종제16주기급여뢰파매소、PD98059화뢰파매소+PD98059복강주사,공8주;지24주처사실험동물,측산종류체적,이HE염색판단종류발생솔;응용면역조화법검측종류조직mTOR、p70s6K、4E-BPl단백적린산화수평.결과:뢰파매소、PD98059급뢰파매소+PD98059간예조소서결직장암발생솔현저저우모형조(44.44%、38.89%、6.67%비77.78%,P균<0.05);종류체적현저소우모형조[분별위(6.153±2.192)、(8.85±3.983)、(2.917±0.191)비(16.136±6.855)mm3,P치균<0.05];단백린산화수평현저저우모형조,mTOR단백린산화수평분별위69.584%±3.600%、72.381%±8.561%、14.430%±2.413%비91.689%±1.994%;p70s6K분별위84.315%±3.132%、81.183%±3.980%、12.135%±2.382%비91.451%±2.160%;4E-BPl분별위65.288%±4.259%、66.641%±4.296%、19.119%±6.297%비75.999%±4.417%(P균<0.05).차재강저종류발생솔、축소종류체적이급억제mTOR신호통로활성방면,뢰파매소+PD98059간예조적효과현저우우뢰파매소급PD98059단독용약,차이유통계학의의(P균<0.05).결론:뢰파매소여PD98059가연합억제소서결직장암적발생화생장,기작용궤제가능섭급대mTOR신호전도통로상관단백린산화수평적억제
Objective To investigate the combined inhibition effect and the potential mechanism of rapamycin (mammalian target of rapamycin inhibitor) and PD98059 (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor) on mouse colorectal cancer (CRC). Methods S-ICR mice were subcutaneously injected with 20 mg/kg of 1,2-dimethylhydrazine dihydrochloride in the nape for 20 weeks to induce CRC. From the 16th week, the mice were treated with alone or combined injection with 0.25 mg/kg rapamycin and 2.5 mg/kg PD98059. The drugs were administered for 8 weeks. Subsequently, the animals were sacrificed and dissected, the tumor sizes were measured, and the tumors were harvested for pathological assay. Furthermore, the phosphorylation of mTOR, p70S6K, and 4E-BPl proteins was detected by using immunohistoehemistry. Results The mice treated with rapamycin (44. 44 %) or PD 98059 (either alone (38.89%) or combination treatment (6.67%) were significantly less likely to develop cancer compared with mice receiving none of them (77.78%, P<0. 05). The average size of tumors was (6.15±2. 192), (8.85±3. 983), (2.917±0. 191), (16.36±6.855) mm3 respectively (P<0.05).The anti-cancer effect of the combination treatment was substantially significant. The proteins of phospho-mTOR, phospho-p70s6K and phospho-4E-BPl were significantly down-regulated after treatments (all P values < ,0.05). Conclusions Combined treatment was more effective than single-drug treatments of rapamycin or PD98059 alone for the prevention and treatment of mouse CRC. The mTOR signal pathway might be involved in the inhibitory mechanism.