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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 Buchholz2,
  6. Georg Feldmann3,4,
  7. Emily P Slater1,
  8. Anirban Maitra3,4,
  9. Detlef K Bartsch1
  1. 1Department of Surgery, Philipps-University Marburg, Germany
  2. 2Department of Gastroenterology and Endocrinology, Philipps-University Marburg, Germany
  3. 3Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  4. 4The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  1. Correspondence to Dr Volker Fendrich, Department of Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, 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 (ACE inhibitors) have potential chemopreventive properties. In this study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the chemopreventive potential of these drugs.

Methods Drug treatment was initiated at the age of 5 weeks. 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 3 and 5 months, animals were killed. The effect of aspirin and enalapril was evaluated by histopathological analyses, immunostaining, and real-time PCR.

Results After 3 and 5 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 enalapril and aspirin. Invasive pancreatic cancer was identified in 15 of 25 (60%) LsL-KrasG12D; LsL-Trp53R172H; Pdx1-Cre untreated control mice, but in only three of 17 (17.6%, p=0.01) mice treated with aspirin, in four of 17 (23.5%, p=0.03) in mice treated with enalapril alone, and in five of 16 (31.2%, p=0.11) mice treated with a combination of both drugs. Using real-time PCR we found a significant downregulation 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. This study together supports the hypothesis that aspirin and ACE inhibitors might be a valid chemopreventive strategy.

  • Pancreatic cancer
  • PanINs
  • chemoprevention
  • ACE-inhibitor
  • enalapril
  • aspirin

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Footnotes

  • Linked articles 200733.

  • Funding VF was supported by a Research Grant of the University Medical Center Giessen and Marburg. GF was supported by a fellowship grant within the postdoctorate programme of the German Academic Exchange Service (DAAD).

  • Competing interests None.

  • Ethics approval All experiments using mice were approved by the local committees for animal care and use.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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