Efficacy of dimethylaminoparthenolide and sulindac in combination with gemcitabine in a genetically engineered mouse model of pancreatic cancer

Michele Yip-Schneider, Huangbing Wu, Ralph H. Hruban, Andrew M. Lowy, Peter A. Crooks, C. Schmidt

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

OBJECTIVES: Pancreatic cancer remains one of the deadliest diseases, with limited surgical and treatment options. Two targets of interest include the transcription factor nuclear factor-κB and cyclooxygenase-2, which are constitutively activated and overexpressed, respectively, in human pancreatic adenocarcinoma. We have previously shown that dimethylaminoparthenolide (DMAPT), a bioavailable nuclear factor-κB inhibitor, and the cyclooxygenase inhibitors sulindac and celecoxib have potential chemotherapeutic efficacy. The current study evaluates the efficacy of intervention with DMAPT and sulindac in the LSL-Kras;Pdx-1-Cre genetically engineered mouse model. Gemcitabine, traditionally a chemotherapeutic agent, has relatively low toxicity; thus, combinations with low-dose gemcitabine were also explored. METHODS: LSL-Kras;Pdx-1-Cre mice at 7 months of age were randomized into placebo, DMAPT (40 mg/kg per day), sulindac (20 mg/kg per day), gemcitabine (50 mg/kg twice weekly), and combination treatment groups. After 3 months of treatment, the mice were killed. RESULTS: The percentage of normal pancreatic ducts was significantly increased by the combinations of DMAPT/sulindac, DMAPT/gemcitabine, sulindac/gemcitabine, and DMAPT/sulindac/gemcitabine compared to placebo. Additionally, the percentage of mouse pancreatic intraepithelial neoplasia-2 lesions was significantly decreased by DMAPT/gemcitabine. CONCLUSIONS: Intervention with DMAPT and sulindac in combination with gemcitabine may delay or prevent progression of premalignant pancreatic lesions in the LSL-Kras;Pdx-1-Cre mouse model of pancreatic cancer.

Original languageEnglish
Pages (from-to)160-167
Number of pages8
JournalPancreas
Volume42
Issue number1
DOIs
StatePublished - Jan 2013

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gemcitabine
Sulindac
Pancreatic Neoplasms
Celecoxib
Placebos
Cyclooxygenase Inhibitors
Pancreatic Ducts
Cyclooxygenase 2

Keywords

  • COX-2
  • gemcitabine
  • NF-JB
  • pancreatic cancer
  • parthenolide
  • sulindac

ASJC Scopus subject areas

  • Hepatology
  • Internal Medicine
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Efficacy of dimethylaminoparthenolide and sulindac in combination with gemcitabine in a genetically engineered mouse model of pancreatic cancer. / Yip-Schneider, Michele; Wu, Huangbing; Hruban, Ralph H.; Lowy, Andrew M.; Crooks, Peter A.; Schmidt, C.

In: Pancreas, Vol. 42, No. 1, 01.2013, p. 160-167.

Research output: Contribution to journalArticle

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abstract = "OBJECTIVES: Pancreatic cancer remains one of the deadliest diseases, with limited surgical and treatment options. Two targets of interest include the transcription factor nuclear factor-κB and cyclooxygenase-2, which are constitutively activated and overexpressed, respectively, in human pancreatic adenocarcinoma. We have previously shown that dimethylaminoparthenolide (DMAPT), a bioavailable nuclear factor-κB inhibitor, and the cyclooxygenase inhibitors sulindac and celecoxib have potential chemotherapeutic efficacy. The current study evaluates the efficacy of intervention with DMAPT and sulindac in the LSL-Kras;Pdx-1-Cre genetically engineered mouse model. Gemcitabine, traditionally a chemotherapeutic agent, has relatively low toxicity; thus, combinations with low-dose gemcitabine were also explored. METHODS: LSL-Kras;Pdx-1-Cre mice at 7 months of age were randomized into placebo, DMAPT (40 mg/kg per day), sulindac (20 mg/kg per day), gemcitabine (50 mg/kg twice weekly), and combination treatment groups. After 3 months of treatment, the mice were killed. RESULTS: The percentage of normal pancreatic ducts was significantly increased by the combinations of DMAPT/sulindac, DMAPT/gemcitabine, sulindac/gemcitabine, and DMAPT/sulindac/gemcitabine compared to placebo. Additionally, the percentage of mouse pancreatic intraepithelial neoplasia-2 lesions was significantly decreased by DMAPT/gemcitabine. CONCLUSIONS: Intervention with DMAPT and sulindac in combination with gemcitabine may delay or prevent progression of premalignant pancreatic lesions in the LSL-Kras;Pdx-1-Cre mouse model of pancreatic cancer.",
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