title: Eflornithine (DFMO) prevents progression of pancreatic cancer by modulating ornithine decarboxylase signaling.
abstract: Ornithine decarboxylase (ODC) is the key rate-limiting enzyme in the polyamine synthesis pathway and it is overexpressed in a variety of cancers. We found that polyamine synthesis and modulation of ODC signaling occurs at early stages of pancreatic precursor lesions and increases as the tumor progresses in Kras-activated p48(Cre/+)-LSL-Kras(G12D/+) mice. Interest in use of the ODC inhibitor eflornithine (DFMO) as a cancer chemopreventive agent has increased in recent years since ODC was shown to be transactivated by the c-myc oncogene and to cooperate with the ras oncogene in malignant transformation of epithelial tissues. We tested the effects of DFMO on pancreatic intraepithelial neoplasias (PanIN) and their progression to pancreatic ductal adenocarcinoma (PDAC) in genetically engineered Kras mice. The Kras(G12D/+) mice fed DFMO at 0.1% and 0.2% in the diet showed a significant inhibition (P < 0.0001) of PDAC incidence compared with mice fed control diet. Pancreatic tumor weights were decreased by 31% to 43% (P < 0.03-0.001) with both doses of DFMO. DFMO at 0.1% and 0.2% caused a significant suppression (27% and 31%; P < 0.02-0.004) of PanIN 3 lesions (carcinoma in situ). DFMO-treated pancreas exhibited modulated ODC pathway components along with decreased proliferation and increased expression of p21/p27 as compared with pancreatic tissues derived from mice fed control diet. In summary, our preclinical data indicate that DFMO has potential for chemoprevention of pancreatic cancer and should be evaluated in other PDAC models and in combination with other drugs in anticipation of future clinical trials.
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. cv-rao@ouhsc.edu altaf-mohammed@ouhsc.edu.
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Naveena B
authors.initials: NB
authors.lastname: Janakiram
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Venkateshwar
authors.initials: V
authors.lastname: Madka
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Rebekah L
authors.initials: RL
authors.lastname: Ritchie
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Misty
authors.initials: M
authors.lastname: Brewer
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Laura
authors.initials: L
authors.lastname: Biddick
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Jagan Mohan R
authors.initials: JM
authors.lastname: Patlolla
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Michael
authors.initials: M
authors.lastname: Sadeghi
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.affiliation: Division of Cancer Prevention, Chemopreventive Agent Development Research Group, National Cancer Institute, Bethesda, Maryland.
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. cv-rao@ouhsc.edu altaf-mohammed@ouhsc.edu.
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D049109:Cell Proliferation; D018450:Disease Progression; D000518:Eflornithine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009955:Ornithine Decarboxylase / Q000737:chemistry* / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D065108:Ornithine Decarboxylase Inhibitors; D012333:RNA, Messenger; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D009955:Ornithine Decarboxylase; D000518:Eflornithine