Rapamycin and PD98059 collaborative inhibit mammalian target of rapamycin pathway in the prevention and treatment of mouse colorectal cancer
10.3760/cma.j.issn.0254-1432.2009.02.011
- VernacularTitle:雷帕霉素与PD98059联合抑制小鼠结直肠癌雷帕霉素靶蛋白信号转导通路
- Author:
Yanjie ZHANG
;
Xiaoqing TIAN
;
Xiaoqiang LI
;
Guangye DU
;
Lingjuan LU
;
Junbo DONG
;
Jingyuan FANG
- Publication Type:Journal Article
- Keywords:
Colorectal neoplasms;
Sirolimus;
Mouse
- From:
Chinese Journal of Digestion
2009;29(2):109-113
- CountryChina
- Language:Chinese
-
Abstract:
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.
