The triterpenoid CDDO-imidazolide reduces immune cell infiltration and cytokine secretion in the KrasG12D;Pdx1-Cre (KC) mouse model of pancreatic cancer.

Abstract

Because the 5-year survival rate for pancreatic cancer remains under 10%, new drugs are needed for the prevention and treatment of this devastating disease. Patients with chronic pancreatitis have a 12-fold higher risk of developing pancreatic cancer. LSL-KrasG12D/+;Pdx-1-Cre (KC) mice replicate the genetics, symptoms and histopathology found in human pancreatic cancer. Immune cells infiltrate into the pancreas of these mice and produce inflammatory cytokines that promote tumor growth. KC mice are particularly sensitive to the effects of lipopolysaccharide (LPS), as only 48% of KC mice survived an LPS challenge while 100% of wildtype (WT) mice survived. LPS also increased the percentage of CD45+ immune cells in the pancreas and immunosuppressive Gr1+ myeloid-derived suppressor cell in the spleen of these mice. The triterpenoid CDDO-imidazolide (CDDO-Im) not only reduced the lethal effects of LPS (71% survival) but also decreased the infiltration of CD45+ cells into the pancreas and the percentage of Gr1+ myeloid-derived suppressor cell in the spleen of KC mice 4-8 weeks after the initial LPS challenge. While the levels of inflammatory cytokine levels were markedly higher in KC mice versus WT mice challenged with LPS, CDDO-Im significantly decreased the production of IL-6, CCL-2, vascular endothelial growth factor and G-CSF in the KC mice. All of these cytokines are prognostic markers in pancreatic cancer or play important roles in the progression of this disease. Disrupting the inflammatory process with drugs such as CDDO-Im might be useful for preventing pancreatic cancer, especially in high-risk populations.

• Authors: Ana S Leal, Michael B Sporn, Patricia A Pioli, Karen T Liby
• Journal: Carcinogenesis (Carcinogenesis) Vol. 37 Issue 12 Pg. 1170-1179 (Dec 2016) ISSN: 1460-2180 [Electronic] England
• PMID: 27659181 (Publication Type: Journal Article)
• Copyright: © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• Ccl12 protein, mouse
• Homeodomain Proteins
• Imidazoles
• Interleukin-6
• Lipopolysaccharides
• Monocyte Chemoattractant Proteins
• Trans-Activators
• Vascular Endothelial Growth Factor A
• pancreatic and duodenal homeobox 1 protein
• vascular endothelial growth factor A, mouse
• Granulocyte Colony-Stimulating Factor
• Oleanolic Acid
• Leukocyte Common Antigens
• Ptprc protein, mouse
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Granulocyte Colony-Stimulating Factor (biosynthesis)
• Homeodomain Proteins (genetics)
• Humans
• Imidazoles (administration & dosage)
• Inflammation (chemically induced, drug therapy, genetics)
• Interleukin-6 (biosynthesis)
• Leukocyte Common Antigens (biosynthesis)
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Knockout
• Monocyte Chemoattractant Proteins (biosynthesis)
• Neoplasms, Experimental (chemically induced, drug therapy, genetics)
• Oleanolic Acid (administration & dosage, analogs & derivatives)
• Pancreas (drug effects, immunology, pathology)
• Pancreatic Neoplasms (chemically induced, drug therapy, genetics)
• Pancreatitis, Chronic (complications, pathology)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Trans-Activators (genetics)
• Vascular Endothelial Growth Factor A (biosynthesis)