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: Altaf Mohammed, Naveena B Janakiram, Venkateshwar Madka, Rebekah L Ritchie, Misty Brewer, Laura Biddick, Jagan Mohan R Patlolla, Michael Sadeghi, Stan Lightfoot, Vernon E Steele, Chinthalapally V Rao
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 7 Issue 12 Pg. 1198-209 (Dec 2014) ISSN: 1940-6215 [Electronic] United States
• PMID: 25248858 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Ornithine Decarboxylase Inhibitors
• RNA, Messenger
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)
• Ornithine Decarboxylase
• Eflornithine

Topics

• Animals
• Apoptosis
• Blotting, Western
• Carcinoma, Pancreatic Ductal (drug therapy, enzymology, pathology)
• Cell Proliferation
• Disease Progression
• Eflornithine (pharmacology)
• Female
• Humans
• Immunoenzyme Techniques
• Male
• Mice
• Mice, Inbred C57BL
• Mutation (genetics)
• Ornithine Decarboxylase (chemistry, metabolism)
• Ornithine Decarboxylase Inhibitors (pharmacology)
• Pancreatic Neoplasms (drug therapy, enzymology, pathology)
• Proto-Oncogene Proteins p21(ras) (physiology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays