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.
OBJECTIVE
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-Kras(G12D); Pdx1-Cre or LsL-Kras(G12D); LsL-Trp53(R172H); 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-Kras(G12D); Pdx1-Cre mice. Furthermore, development of invasive pancreatic cancer in LsL-Kras(G12D); LsL-Trp53(R172H); Pdx1-Cre transgenic mice was partially inhibited by enalapril and aspirin. Invasive pancreatic cancer was identified in 15 of 25 (60%) LsL-Kras(G12D); LsL-Trp53(R172H); 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.


CONCLUSIONS
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.
Fendrich
Volker
V
Department of Surgery, Philipps University Marburg, Baldingerstrasse, Marburg, Germany. fendrich@med.uni-marburg.de
Chen
Nai-Ming
NM
Neef
Meike
M
Waldmann
Jens
J
Buchholz
Malte
M
Feldmann
Georg
G
Slater
Emily P
EP
Maitra
Anirban
A
Bartsch
Detlef K
DK
D000681:Amylases / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004656:Enalapril / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D016588:Anticarcinogenic Agents; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D004656:Enalapril; D000681:Amylases; D001241:Aspirin