Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer

Karen T. Liby, Darlene B. Royce, Renee Risingsong, Charlotte R. Williams, Anirban Maitra, Ralph H Hruban, Michael B. Sporn

Research output: Contribution to journalArticle

Abstract

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States and is nearly always fatal. Whereas early detection offers the most promising approach for reducing the mortality of this disease, there is still a need to develop effective drugs for the prevention and treatment of pancreatic cancer. We tested two promising classes of noncytotoxic drugs, synthetic oleanane triterpenoids and rexinoids, for the prevention of carcinogenesis in the highly relevant LSL-KrasG12D/+;LSL-Trp53 R127H/+; Pdx-1-Cre (KPC) mouse model of pancreatic cancer. KPC transgenic mice closely recapitulate the genetic mutations, clinical symptoms, and histopathology found in human pancreatic cancer. Beginning at 4 weeks of age, mice were fed powdered control diet or a diet containing the triterpenoids CDDO-methyl ester (CDDO-Me) or CDDO-ethyl amide, the rexinoid LG100268 (LG268), or the combination, until the mice displayed overt symptoms of pancreatic cancer. CDDO-Me, LG268, the combination of CDDO-Me and LG268, and the combination of CDDO-ethyl amide and LG268, all significantly (P <0.05) increased survival in the KPC mice by 3 to 4 weeks. Recent studies have shown that gemcitabine, the current standard of care for human pancreatic cancer, does not extend survival in KPC mice. In cell lines developed from the KPC mice, the triterpenoids directly interact with both signal transducer and activator of transcription 3 and I?B kinase (IKK) to decrease constitutive interleukin-6 secretion, inhibit constitutive signal transducer and activator of transcription 3 phosphorylation, and block the degradation of I?B? when challenged with tumor necrosis factor ?. These results suggest that oleanane triterpenoids and rexinoids have the potential to prevent pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1427-1434
Number of pages8
JournalCancer Prevention Research
Volume3
Issue number11
DOIs
StatePublished - Nov 2010

Fingerprint

Pancreatic Neoplasms
Transgenic Mice
Survival
STAT3 Transcription Factor
gemcitabine
Diet
Standard of Care
Pharmaceutical Preparations
Interleukin-6
Carcinogenesis
Phosphotransferases
Tumor Necrosis Factor-alpha
Phosphorylation
Cell Line
Mutation
Mortality
LG 100268
methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer. / Liby, Karen T.; Royce, Darlene B.; Risingsong, Renee; Williams, Charlotte R.; Maitra, Anirban; Hruban, Ralph H; Sporn, Michael B.

In: Cancer Prevention Research, Vol. 3, No. 11, 11.2010, p. 1427-1434.

Research output: Contribution to journalArticle

Liby, Karen T. ; Royce, Darlene B. ; Risingsong, Renee ; Williams, Charlotte R. ; Maitra, Anirban ; Hruban, Ralph H ; Sporn, Michael B. / Synthetic triterpenoids prolong survival in a transgenic mouse model of pancreatic cancer. In: Cancer Prevention Research. 2010 ; Vol. 3, No. 11. pp. 1427-1434.
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