title: Prolonged survival and delayed progression of pancreatic intraepithelial neoplasia in LSL-KrasG12D/+;Pdx-1-Cre mice by vitamin E δ-tocotrienol.
abstract: The highly lethal nature of pancreatic cancer and the increasing recognition of high-risk individuals have made research into chemoprevention a high priority. Here, we tested the chemopreventive activity of δ-tocotrienol, a bioactive vitamin E derivative extracted from palm fruit, in the LSL-Kras(G12D/+);Pdx-1-Cre pancreatic cancer mouse model. At 10 weeks of age, mice (n = 92) were randomly allocated to three groups: (i) no treatment; (ii) vehicle and (iii) δ-tocotrienol (200mg/kg × 2/day, PO). Treatment was continued for 12 months. Mice treated with δ-tocotrienol showed increased median survival from the onset of treatment (11.1 months) compared with vehicle-treated mice (9.7 months) and non-treated mice (8.5 months; P < 0.025). Importantly, none of the mice treated with δ-tocotrienol harbored invasive cancer compared with 10% and 8% in vehicle-treated and non-treated mice, respectively. Furthermore, δ-tocotrienol treatment also resulted in significant suppression of mouse pancreatic intraepithelial neoplasm (mPanIN) progression compared with vehicle-treated and non-treated mice: mPanIN-1: 47-50% (P < 0.09), mPanIN-2: 6-11% (P < 0.001), mPanIN-3: 3-15% (P < 0.001) and invasive cancer: 0-10% (P < 0.001). δ-Tocotrienol treatment inhibited mutant Kras-driven pathways such as MEK/ERK, PI3K/AKT and NF-kB/p65, as well as Bcl-xL and induced p27. δ-Tocotrienol also induced biomarkers of apoptosis such as Bax and activated caspase 3 along with an increase in plasma levels of CK18. In summary, δ-tocotrienol's ability to interfere with oncogenic Kras pathways coupled with the observed increase in median survival and significant delay in PanIN progression highlights the chemopreventative potential of δ-tocotrienol and warrants further investigation of this micronutrient in individuals at high risk for pancreatic cancer.
authors.affiliation: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Kazim
authors.initials: K
authors.lastname: Husain
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Centeno
authors.forename: Dung-Tsa
authors.initials: DT
authors.lastname: Chen
authors.forename: William J
authors.initials: WJ
authors.lastname: Fulp
authors.forename: Marta
authors.initials: M
authors.lastname: Perez
authors.forename: Guo
authors.initials: G
authors.lastname: Zhang Lee
authors.forename: Noreen
authors.initials: N
authors.lastname: Luetteke
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Mokenge P
authors.initials: MP
authors.lastname: Malafa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D002278:Carcinoma in Situ / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D053148:Caspase 3 / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000187:drug effects / Q000235:genetics; D013534:Survival; D015534:Trans-Activators / Q000235:genetics; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D053148:Caspase 3; D048049:Extracellular Signal-Regulated MAP Kinases; D018398:Homeodomain Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D015534:Trans-Activators; D051996:Transcription Factor RelA; D014810:Vitamin E; D051020:bcl-X Protein; C494812:Bcl2l1 protein, mouse; C498144:Rela protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C082097:tocotrienol, delta; C495971:Hras protein, mouse