Abstract
Background
Observational studies demonstrate a protective effect of statins on the development and progression of esophageal adenocarcinoma. The role of statins in the prevention of reflux-induced esophageal changes remains unknown.
Aims
Using a mixed gastroduodenal reflux mouse model, we hypothesized that oral administration of simvastatin would attenuate reflux-induced mucosal changes of the distal esophagus.
Methods
Human Barrett’s (CPB) and esophageal adenocarcinoma (FLO1 and OE19) cells were treated with simvastatin. Cell proliferation and apoptosis were evaluated using the MTS proliferation and annexin V apoptosis assays, respectively. A reflux mouse model was generated by performing a side-to-side anastomosis between the gastroesophageal junction and first portion of the duodenum (duodeno-gastroesophageal anastomosis, DGEA). DGEA mice were fed a standard or simvastatin-containing diet following surgery. Mice were euthanized 6 weeks post-operatively.
Results
Simvastatin significantly decreased proliferation and increased apoptosis in all cell lines. Compared to control animals, mice undergoing DGEA who were fed a standard diet demonstrated a fourfold increase in mucosal thickness and significant increase in proliferating cells (p < 0.0001). DGEA mice fed a simvastatin-containing diet had an attenuated response to reflux, with a significant reduction in mucosal hyperplasia and proliferation (p < 0.0001). DGEA mice fed a simvastatin-containing diet demonstrated significant upregulation of procaspase-3 (p = 0.009) and cleaved caspase-3 (p = 0.034) in the distal esophagus.
Conclusions
We demonstrate for the first time a reduction in reflux-induced histologic changes of the distal esophagus following oral administration of simvastatin in vivo. These findings identify simvastatin as a potential preventative agent to inhibit the development and progression of reflux-induced esophageal injury.
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References
Ogunwobi OO, Beales IL. Statins inhibit proliferation and induce apoptosis in Barrett’s esophageal adenocarcinoma cells. Am J Gastroenterol 2008;103:825–837.
Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des 2012;18:1519–1530.
Diamantis E, Kyriakos G, Quiles-Sanchez LV, Farmaki P, Troupis T. The anti-inflammatory effects of statins on coronary artery disease: an updated review of the literature. Curr Cardiol Rev 2017;13:209–216.
Graaf MR, Richel DJ, van Noorden CJF, Guchelaar H-J. Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer Treat Rev 2004;30:609–641.
Boudreau DM, Yu O, Johnson J. Statin use and cancer risk: a comprehensive review. Expert Opin Drug Saf 2010;9:603–621.
Fatehi HA. Current perspectives on statins as potential anti-cancer therapeutics: clinical outcomes and underlying molecular mechanisms. Transl Lung Cancer Res 2019;8:692–699.
Konturek PC, Burnat G, Hahn EG. Inhibition of Barret’s adenocarcinoma cell growth by simvastatin: involvement of COX-2 and apoptosis-related proteins. J Physiol Pharmacol 2007;58:141–148.
Sadaria MR, Reppert AE, Yu JA, Meng X, Fullerton DA, Reece TB et al. Statin therapy attenuates growth and malignant potential of human esophageal adenocarcinoma cells. J Thorac Cardiovasc Surg 2011;142:1152–1160.
Chen Y, Li L-B, Zhang J, Tang D-P, Wei J-J, Zhuang Z-H. Simvastatin, but not pravastatin, inhibits the proliferation of esophageal adenocarcinoma and squamous cell carcinoma cells: a cell-molecular study. Lipids Health Dis 2018;17:290.
Yu JA, Li H, Meng X, Fullerton DA, Nemenoff RA, Mitchell JD et al. Group IIa secretory phospholipase expression correlates with group IIa secretory phospholipase inhibition-mediated cell death in K-ras mutant lung cancer cells. J Thorac Cardiovasc Surg 2012;144:1479–1485.
Babu A, Meng X, Banerjee AM, Gamboni-Robertson F, Cleveland JC, Damle S et al. Secretory phospholipase A2 is required to produce histologic changes associated with gastroduodenal reflux in a murine model. J Thorac Cardiovasc Surg 2008;135:1220–1227.
McKay A, Leung BP, McInnes IB, Thomson NC, Liew FY. A novel anti-inflammatory role of simvastatin in a murine model of allergic asthma. J Immunol 2004;172:2903–2908.
Bruner-Tran KL, Osteen KG, Duleba AJ. Simvastatin protects against the development of endometriosis in a nude mouse model. J Clin Endocrinol Metab 2009;94:2489–2494.
Zhang X, Mao S, Luo G, Wei J, Berggren-Söderlund M, Nilsson-Ehle P et al. Effects of simvastatin on apolipoprotein M in vivo and in vitro. Lipids Health Dis 2011;10:112.
Highlights of Prescribing Information. Zocor (simvastatin) Tablets. Merck Sharp & Dohme LTD. 2015.
Gergen AK, Kohtz PD, Halpern AL, et al. Statins inhibit toll-like receptor 4-mediated growth of human esophageal adenocarcinoma cells. J Surg Res. 2021;260:436–447. https://doi.org/10.1016/j.jss.2020.11.016
Thomas T, Loke Y, Beales ILP. Systematic review and meta-analysis: use of statins is associated with a reduced incidence of oesophageal adenocarcinoma. J Gastrointest Cancer 2018;49:442–454.
Singh S, Singh AG, Singh PP, Murad MH, Iyer PG. Statins are associated with reduced risk of esophageal cancer, particularly in patients with Barrett’s esophagus: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2013;11:620–629.
Deng H-Y, Lan X, Zheng X, Zha P, Zhou J, Wang R-L et al. The association between statin use and survival of esophageal cancer patients: a systematic review and meta-analysis. Medicine 2019;98:e16480.
Zhang HY, Spechler SJ, Souza RF. Esophageal adenocarcinoma arising in Barrett esophagus. Cancer Lett 2009;275:170–177.
Goldstein SR, Yang GY, Curtis SK, Reuhl KR, Liu BC, Mirvish SS et al. Development of esophageal metaplasia and adenocarcinoma in a rat surgical model without the use of a carcinogen. Carcinogenesis 1997;18:2265–2270.
Chen X, Yang G, Ding WY, Bondoc F, Curtis SK, Yang CS. An esophagogastroduodenal anastomosis model for esophageal adenocarcinogenesis in rats and enhancement by iron overload. Carcinogenesis 1999;20:1801–1808.
Garman KS, Orlando RC, Chen X. Review: experimental models for Barrett’s esophagus and esophageal adenocarcinoma. Am J Physiol Gastrointest Liver Physiol 2012;302:G1231–G1243.
He J, Fang Y, Chen X. Surgical models of gastroesophageal reflux with mice. J Vis Exp 2015;102:e53012–e53112.
Mason RP. Molecular basis of differences among statins and a comparison with antioxidant vitamins. Am J Cardiol 2006;98:S34–S41.
Funding
This work was funded by the University of Colorado School of Medicine Department of Surgery, Division of Cardiothoracic Surgery.
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All applicable international and national guidelines for the care and use of animals were followed. Ethical approval was granted by the Institutional Animal Care and Use Committee at the University of Colorado (protocol #00893).
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Gergen, A.K., Madsen, H.J., Li, A. et al. Simvastatin Inhibits Histologic Changes Associated with Gastroduodenal Reflux in a Murine Model. Dig Dis Sci 67, 4732–4741 (2022). https://doi.org/10.1007/s10620-021-07344-0
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DOI: https://doi.org/10.1007/s10620-021-07344-0