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The Angiotensin-I-converting Enzyme Inhibitor Enalapril and Aspirin delay progression of Pancreatic Intraepithelial Neoplasia and cancer formation in a genetically engineered mouse model of pancreatic cancer
  1. Volker Fendrich1,*,
  2. Nai-Ming Chen1,
  3. Meike Neef1,
  4. Jens Waldmann1,
  5. Malte Bucholz2,
  6. Georg Feldmann3,
  7. Emily P Slater1,
  8. Anirban Maitra3,
  9. Detlef K Bartsch1
  1. 1 Department of Surgery, Philipps-University Marburg, Germany;
  2. 2 Department of Gastroenterology and Endocrinology, Philipps-University Marburg, Germany;
  3. 3 Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Germany
  1. Correspondence to: Volker Fendrich, Surgery, University of Marburg, Baldingerstrasse, Marburg, 35043, Germany; fendrich{at}med.uni-marburg.de

Abstract

Background and aims: There are no chemopreventive strategies for pancreatic cancer or its precursor lesions, pancreatic intraepithelial neoplasia (PanINs). Recent evidence suggests that aspirin and inhibitors of angiotensin-I converting enzyme have chemopreventive properties. In this study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the chemopreventive potential of these drugs.

Methods: LsL-KrasG12D; Pdx1-Cre or LsL-KrasG12D; LsL-Trp53R172H; Pdx1-Cre transgenic mice were randomly assigned to receive either mock treatment, aspirin, enalapril, or a combination of both. After three and five months, animals were sacrificed. The effect of aspirin and enalapril was evaluated by histopathological analyses, immunostaining, and real-time PCR.

Results: After three and five months of treatment, enalapril and aspirin were able to significantly delay progression of mPanINs in LsL-KrasG12D; Pdx1-Cre mice. Furthermore, development of invasive pancreatic cancer in LsL-KrasG12D; LsL-Trp53R172H; Pdx1-Cre transgenic mice was partially inhibited by. Invasive pancreatic cancer was identified in 15 of 25 (60%) LsL-KrasG12D; LsL-Trp53R172H; Pdx1-Cre untreated mice, but in only 3 of 17 (17.6%, p=0.01) mice treated with aspirin, in 4 of 17 (23.5%, p=0.03) in mice treated with Enalapril alone, and in 5 of 16 (31.2%, p=0.11) mice treated with a combination of both drugs. Using real-time PCR we found a significant down-regulation of the target genes VEGF and RelA demonstrating our ability to achieve effective pharmacological levels of aspirin and enalapril during pancreatic cancer formation in vivo.

Conclusion: Using a transgenic mouse model that imitates human pancreatic cancer, this study provides first evidence that aspirin and enalapril are effective chemopreventive agents by delaying the progression of PanINs and partially inhibiting the formation of murine pancreatic cancer.

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