title: Early and delayed intervention with rapamycin prevents NNK-induced lung adenocarcinoma in A/J mice.
abstract: 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-(methylnitrosamino)-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 μmol 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 <~0.75 mm3 (p=0.0056). Lung tumors harvested from mice exposed to rapamycin showed a significant decrease in p-mTOR, p-S6K1, PCNA and Bcl-xL as compared with controls in the early and late stage intervention studies. These observations suggest that rapamycin is highly effective even with administration after dysplastic adenoma or early adenocarcinoma stages and is useful for high-risk lung cancer patients.
authors.affiliation: Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Jagan M R
authors.initials: JM
authors.lastname: Patlolla
authors.affiliation: Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892-9788, USA.
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.affiliation: Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.affiliation: Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Venkateshwar
authors.initials: V
authors.lastname: Madka
authors.affiliation: Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.affiliation: Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Biddick
authors.affiliation: Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Sadeghi
authors.affiliation: Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.affiliation: Center for Chemoprevention and Cancer Drug Development, Department of Medicine, Hem-Onc Section, PCS Oklahoma Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009538:Nicotine / Q000009:adverse effects; D009602:Nitrosamines / Q000633:toxicity; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000096:biosynthesis; D020123:Sirolimus / Q000008:administration & dosage*; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis; D014026:Nicotiana / Q000009:adverse effects*; D051020:bcl-X Protein / Q000096:biosynthesis
chemical_list: C494812:Bcl2l1 protein, mouse; D002273:Carcinogens; D009602:Nitrosamines; D018809:Proliferating Cell Nuclear Antigen; D051020:bcl-X Protein; D009538:Nicotine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C546842:MTOR protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus