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Vitamin E δ-Tocotrienol Prolongs Survival in the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) Transgenic Mouse Model of Pancreatic Cancer
- Source :
- Cancer Prevention Research. 6:1074-1083
- Publication Year :
- 2013
- Publisher :
- American Association for Cancer Research (AACR), 2013.
-
Abstract
- Previous work has shown that vitamin E δ-tocotrienol (VEDT) prolongs survival and delays progression of pancreatic cancer in the LSL-KrasG12D/+;Pdx-1-Cre mouse model of pancreatic cancer. However, the effect of VEDT alone or in combination with gemcitabine in the more aggressive LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model is unknown. Here, we studied the effects of VEDT and the combination of VEDT and gemcitabine in the KPC mice. KPC mice were randomized into four groups: (i) vehicle [olive oil, 1.0 mL/kg per os twice a day and PBS 1.0 mL/kg intrapertoneally (i.p.) twice a week], (ii) gemcitabine (100 mg/kg i.p. twice a week), (iii) VEDT (200 mg/kg per os twice a day), and (iv) gemcitabine + VEDT. Mice received treatment until they displayed symptoms of impending death from pancreatic cancer, at which point animals were euthanized. At 16 weeks, survival was 10% in the vehicle group, 30% in the gemcitabine group, 70% in the VEDT group (P < 0.01), and 90% in the VEDT combined with gemcitabine group (P < 0.05). VEDT alone and combined with gemcitabine resulted in reversal of epithelial-to-mesenchymal transition in tumors. Biomarkers of apoptosis (plasma CK18), PARP1 cleavage, and Bax expression were more greatly induced in tumors subjected to combined treatment versus individual treatment. Combined treatment induced cell-cycle inhibitors (p27Kip1 and p21Cip1) and inhibited VEGF, vascularity (CD31), and oncogenic signaling (pAKT, pMEK, and pERK) greater than individual drugs. No significant differences in body weight gain between drug treatment and control mice were observed. These results strongly support further investigation of VEDT alone and in combination with gemcitabine for pancreatic cancer prevention and treatment. Cancer Prev Res; 6(10); 1074–83. ©2013 AACR.
- Subjects :
- Cyclin-Dependent Kinase Inhibitor p21
Male
Genetically modified mouse
Cancer Research
medicine.medical_specialty
Epithelial-Mesenchymal Transition
Genotype
medicine.medical_treatment
Apoptosis
Enzyme-Linked Immunosorbent Assay
Mice, Transgenic
Biology
Deoxycytidine
Article
Mice
Random Allocation
chemistry.chemical_compound
Internal medicine
Pancreatic cancer
Biomarkers, Tumor
medicine
Animals
Vitamin E
Cell Proliferation
bcl-2-Associated X Protein
Cell growth
Body Weight
medicine.disease
Immunohistochemistry
Gemcitabine
Pancreatic Neoplasms
Platelet Endothelial Cell Adhesion Molecule-1
Disease Models, Animal
Genes, ras
Treatment Outcome
Endocrinology
Oncology
chemistry
Drug Therapy, Combination
Female
Tocotrienol
Poly(ADP-ribose) Polymerases
Cyclin-Dependent Kinase Inhibitor p27
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 19406215 and 19406207
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Cancer Prevention Research
- Accession number :
- edsair.doi.dedup.....1fa65ddcd6578ae5907492325fcea957
- Full Text :
- https://doi.org/10.1158/1940-6207.capr-13-0157