Aspirin und der ACE-Inhibitor Enalapril verzögern die Progression von PanINs und die Entstehung eines invasiven Pankreaskarzinoms im transgenen Tumormausmodell

Abstract

Background and aims: Pancreatic cancer is one of the most dismal of human malignancies. 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: LsL-Kras G12D ; Pdx1-Cre or LsL-Kras G12D ; LsL-Trp53 R172H ; Pdx1-Cre transgenic mice were randomly assigned to receive either A) mock treatment, B) aspirin, C) enalapril, or D) a combination of aspirin and enalapril. 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 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 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. In addition, we found that treatment with aspirin and enalapril prolonged the median survival of LsL-KrasG12D; LsL-Trp53R172H; Pdx1-Cre transgenic mice as compared to mock treated animals (median survival 150 vs. 133 days; p = 0.013). 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. This study together supports the hypothesis that aspirin and ACE-Inhibitors might be a valid chemopreventive strategy.