Early and delayed intervention with Rapamycin prevents NNK-induced lung adenocarcinoma in A/J mice

In tobacco-associated lung cancers, the protein kinase B/mammalian target of rapamycin (Akt/mTOR) pathway frequently is activated by nicotine and its metabolite 4-(methyl nitrosami no)-1-(3-pyridyl)-1-butanone (NNK). The aim of the present study was to examine the effects of early or late intervention with rapamycin in NNK-induced lung adenoma and progression to adenocarcinoma in female A/J mice. At 7 weeks of age, 40 mice/each carcinogen group received one dose of 10 mu mol NNK i.p. Three weeks later, the early intervention groups (25/group) were fed diets containing 0, 8 or 16 ppm rapamycin. The mice were sacrificed after 17 or 34 weeks of drug exposure and tumors were evaluated via histopathology. For late intervention (late adenoma and adenocarcinoma stage), groups of 15 mice were administered diets containing 8 or 16 ppm rapamycin starting 20 weeks after NNK treatment and continuing for 17 weeks before evaluation of tumor progression. Administration of 8 or 16 ppm rapamycin as an early or a late stage intervention significantly suppressed lung adenoma and adenocarcinoma formation (p<0.01-0.0001) after 17 or 34 weeks of exposure. The effect was more pronounced (>50-60% tumor inihibition; p<0.0001) at the early intervention and the size of NNK-induced tumors decreased from >2.10 to