Advertisement

Digestive Diseases and Sciences

, Volume 61, Issue 10, pp 2896–2907 | Cite as

Acetylsalicylic Acid Exhibits Antitumor Effects in Esophageal Adenocarcinoma Cells In Vitro and In Vivo

  • Elena PiazueloEmail author
  • Paula Esquivias
  • Alba De Martino
  • Carmelo Cebrián
  • Blanca Conde
  • Sonia Santander
  • Sonia Emperador
  • María Asunción García-González
  • Patricia Carrera-Lasfuentes
  • Angel Lanas
Original Article

Abstract

Background and Aim

Recent observational studies have shown therapeutic benefits of acetylsalicylic acid (ASA) in several types of cancer. We examined whether ASA exerts antitumor activity in esophageal adenocarcinoma (EAC).

Methods

Human EAC cells (OE33) were treated with ASA (0–5 mM) to evaluate proliferation, apoptosis, and migration. In vivo model: OE33-derived tumors were subcutaneously implanted into athymic mice which were allocated to ASA (5 or 50 mg/kg/day)/vehicle (5–6 animals/group). Tumor growth was assessed every 2–3 days, and after 40 days, mice were euthanized. Plasma drug levels were determined by high-performance liquid chromatography. Histological and immunohistochemical (Ki67, activated caspase-3) analysis of tumors were performed. The effect of ASA on tumor prostaglandin E2 (PGE2) levels was also evaluated.

Results

In vitro cell proliferation and migration were significantly inhibited while apoptosis increased (p < 0.05) by ASA. Although ASA did not induce tumor remission, tumor progression was significantly lower in ASA-treated mice when compared to non-treated animals (478 % in mice treated with 5 mg/kg/day ASA vs. 2696 % control; 748 % in mice treated with 50 mg/kg/day ASA vs. 2670 % control). Maximum tumor inhibition was 92 and 85 %, respectively. This effect was associated with a significant decrease of proliferation index in tumors. ASA 5 mg/kg/day did not modify tumor PGE2 levels. Whereas tumor PGE2 content in mice treated with ASA 50 mg/kg was lower than in control mice, the difference was not significant.

Conclusion

Although these results need to be confirmed in other EAC cells, our data suggest a role for ASA in the treatment of this tumor.

Keywords

Esophageal adenocarcinoma Acetylsalicylic acid Aspirin Cyclooxygenase Prostaglandin E2 Xenografts 

Abbreviations

ASA

Acetyl salicylic acid

SA

Salicylic acid

EAC

Esophageal adenocarcinoma

GERD

Gastroesophageal reflux disease

NSAIDs

Nonsteroidal anti-inflammatory drugs

COX

Cyclooxygenase

TI

Tumor inhibition

Rt

Tumor remission

PGE2

Prostaglandin E2

Notes

Authors’ contribution

Piazuelo E designed the study and wrote the manuscript; Esquivias P performed all biochemical analysis, contributed to animal and in vitro experiments, and to the edition of the manuscript. De Martino A and Cebrián C performed histological and immunohistochemical analysis; Conde B and Emperador S were involved in the experiments in nude mice. Santander S performed in vitro studies; García-González MA was involved in all biochemical determinations and provided vital reagents and analytical tools; Carreras P and Lanas A were involved in the design of the study, statistical analysis, and editing the manuscript.

Compliance with ethical standards

Conflict of interest

AL is advisor to Bayer and has received an investigator initiated grant from Bayer for investigations unrelated to this study. The rest of authors declared that they have no competing interests.

References

  1. 1.
    Blot WJ, Devessa SS, Kneller RW, Fraumeni JF Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA. 1991;265:1287–1289.CrossRefPubMedGoogle Scholar
  2. 2.
    Brown LM, Devesa SS, Chow WH. Incidence of adenocarcinoma of the esophagus among white Americans by sex, stage, and age. J Natl Cancer Inst. 2008;100:1184–1187.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Botterweck AA, Schouten LJ, Volovics A, Dorant E, van Den Brandt PA. Trends in incidence of adenocarcinoma of the oesophagus and gastric cardia in ten European countries. Int J Epidemiol. 2000;29:645–654.CrossRefPubMedGoogle Scholar
  4. 4.
    Lagergren J, Bergström R, Lindgren A, Nyrén O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med. 1999;340:825–831.CrossRefPubMedGoogle Scholar
  5. 5.
    Stein HJ, Siewert JR. Barrett’s esophagus: pathogenesis, epidemiology, functional abnormalities, malignant degeneration, and surgical management. Dysphagia. 1993;8:276–288.CrossRefPubMedGoogle Scholar
  6. 6.
    Polednak AP. Trends in survival for both histologic types of esophageal cancer in US surveillance, epidemiology and end results areas. Int J Cancer. 2003;105:98–100.CrossRefPubMedGoogle Scholar
  7. 7.
    Husain SS, Szabo IL, Tarnawski AS. NSAID inhibition of GI cancer growth: clinical implications and molecular mechanisms of action. Am J Gastroenterol. 2002;97:542–553.CrossRefPubMedGoogle Scholar
  8. 8.
    Cuzick J, Otto F, Baron JA, et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 2009;10:501–507.CrossRefPubMedGoogle Scholar
  9. 9.
    Corley DA, Kerlikowske K, Verma R, Buffler P. Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology. 2003;124:47–56.CrossRefPubMedGoogle Scholar
  10. 10.
    Jayaprakash V, Menezes RJ, Javle MM, et al. Regular aspirin use and esophageal cancer risk. Int J Cancer. 2006;119:202–207.CrossRefPubMedGoogle Scholar
  11. 11.
    Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377:31–41.CrossRefPubMedGoogle Scholar
  12. 12.
    Rockett JC, Larkin K, Darnton SJ, Morris AG, Matthews HR. Five newly established oesophageal carcinoma cell lines: phenotypic and immunological characterization. Br J Cancer. 1997;75:258–263.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Piazuelo E, Jiménez P, Strunk M, et al. Effects of selective PGE2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett’s esophagus. Prostaglandins Other Lipid Mediat. 2006;81:150–161.CrossRefPubMedGoogle Scholar
  14. 14.
    Santander S, Cebrián C, Esquivias P, et al. Cyclooxygenase inhibitors decrease the growth and induce regression of human esophageal adenocarcinoma xenografts in nude mice. Int J Oncol. 2012;40:527–534.PubMedGoogle Scholar
  15. 15.
    Barnes CJ, Lee M. Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin. Gastroenterology. 1998;114:873–877.CrossRefPubMedGoogle Scholar
  16. 16.
    Bousserouel S, Gosse F, Bouhadjar M, Soler L, Marescaux J, Rau F. Long-term administration of aspirin inhibits tumour formation and triggers anti-neoplastic molecular changes in a pre-clinical model of colon carcinogenesis. Oncol Rep. 2010;23:511–517.PubMedGoogle Scholar
  17. 17.
    Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2007;22:659–666.CrossRefPubMedGoogle Scholar
  18. 18.
    Langdon SP, Hendriks HR, Braakhuis BJ, et al. Preclinical phase II studies in human tumor xenografts: a European multicenter follow-up study. Ann Oncol. 1994;5:415–422.CrossRefPubMedGoogle Scholar
  19. 19.
    Jansen WJ, Kolfschoten GM, Erkelens CA, Van Ark-Otte J, Pinedo HM, Boven E. Anti-tumor activity of CPT-11 in experimental human ovarian cancer and human soft-tissue sarcoma. Int J Cancer. 1997;73:891–896.CrossRefPubMedGoogle Scholar
  20. 20.
    Lanas AI, Arroyo MT, Esteva F, Cornudella R, Hirschowitz BI, Sáinz R. Aspirin related gastrointestinal bleeders have an exaggerated bleeding time response due to aspirin use. Gut. 1996;39:654–660.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Pasche B, Wang M, Pennison M, Jimenez H. Prevention and treatment of cancer with aspirin: where do we stand? Semin Oncol. 2014;41:397–401.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Neugut AI. Aspirin as adjuvant therapy for stage III colon cancer: standard of care? JAMA Intern Med. 2014;174:739–741.CrossRefPubMedGoogle Scholar
  23. 23.
    Li P, Wu H, Zhang H, et al. Aspirin use after diagnosis but not prediagnosis improves established colorectal cancer survival: a meta-analysis. Gut. 2014. doi: 10.1136/gutjnl-2014-308260.Google Scholar
  24. 24.
    Langley RE, Burdett S, Tierney JF, Cafferty F, Parmar MK, Venning G. Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy? Br J Cancer. 2011;105:1107–1113.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Langley RE, Rothwell PM. Aspirin in gastrointestinal oncology: new data on an old friend. Curr Opin Oncol. 2014;26:441–447.CrossRefPubMedGoogle Scholar
  26. 26.
    Kmietowicz Z. Study finds possible role for aspirin as treatment for colon cancer. BMJ. 2012;344:e2988.CrossRefPubMedGoogle Scholar
  27. 27.
    Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302:649–658.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Bastiaannet E, Sampieri K, Dekkers OM, et al. Use of aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer. 2012;106:1564–1570.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Reimers MS, Bastiaannet E, van Herk-Sukel MP, et al. Aspirin use after diagnosis improves survival in older adults with colon cancer: a retrospective cohort study. J Am Geriatr Soc. 2012;60:2232–2236.CrossRefPubMedGoogle Scholar
  30. 30.
    Cardwell CR, Kunzmann AT, Cantwell MM, et al. Low-dose aspirin use after diagnosis of colorectal cancer does not increase survival: a case-control analysis of a population-based cohort. Gastroenterology. 2014;146:700–708.CrossRefPubMedGoogle Scholar
  31. 31.
    Holmes MD, Chen WY, Li L, Hertzmark E, Spiegelman D, Hankinson SE. Aspirin intake and survival after breast cancer. J Clin Oncol. 2010;28:1467–1472.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Liu JF, Jamieson GG, Wu TC, Zhu GJ, Drew PA. A preliminary study on the postoperative survival of patients given aspirin after resection for squamous cell carcinoma of the esophagus or adenocarcinoma of the cardia. Ann Surg Oncol. 2009;16:1397–1402.CrossRefPubMedGoogle Scholar
  33. 33.
    Pathi S, Jutooru I, Chadalapaka G, Nair V, Lee SO, Safe S. Aspirin inhibits colon cancer cell and tumor growth and downregulates specificity protein (Sp) transcription factors. PLoS ONE. 2012;7:e48208.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Zhang Y, Liu L, Fan P, et al. Aspirin counteracts cancer stem cell features, desmoplasia and gemcitabine resistance in pancreatic cancer. Oncotarget. 2015;6:9999–10015.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hossain MA, Kim DH, Jang JY, et al. Aspirin induces apoptosis in vitro and inhibits tumor growth of human hepatocellular carcinoma cells in a nude mouse xenograft model. Int J Oncol. 2012;40:1298–1304.PubMedGoogle Scholar
  36. 36.
    Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126:234S–2364S.CrossRefPubMedGoogle Scholar
  37. 37.
    Wang D, Dubois RN. Eicosanoids and cancer. Nat Rev Cancer. 2000;10:181–193.CrossRefGoogle Scholar
  38. 38.
    Bruno A, Dovizio M, Tacconelli S, Patrignani P. Mechanisms of the antitumoural effects of aspirin in the gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2012;26:e1–e13.CrossRefPubMedGoogle Scholar
  39. 39.
    Frommel TO, Dyavanapalli M, Oldham T, et al. Effect of aspirin on prostaglandin E2 and leukotriene B4 production in human colonic mucosa from cancer patients. Clin Cancer Res. 1997;3:209–213.PubMedGoogle Scholar
  40. 40.
    Barnes CJ, Hamby-Mason RL, Hardman WE, Cameron IL, Speeg KV, Lee M. Effect of aspirin on prostaglandin E2 formation and transforming growth factor alpha expression in human rectal mucosa from individuals with a history of adenomatous polyps of the colon. Cancer Epidemiol Biomarkers Prev. 1999;8:311–315.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Elena Piazuelo
    • 1
    • 2
    • 3
    Email author
  • Paula Esquivias
    • 3
  • Alba De Martino
    • 2
  • Carmelo Cebrián
    • 4
  • Blanca Conde
    • 5
  • Sonia Santander
    • 5
  • Sonia Emperador
    • 5
  • María Asunción García-González
    • 1
    • 2
    • 3
  • Patricia Carrera-Lasfuentes
    • 5
  • Angel Lanas
    • 1
    • 3
    • 5
    • 6
  1. 1.IIS AragónSaragossaSpain
  2. 2.Instituto Aragonés de Ciencias de la SaludCentro de Investigación Biomédica de AragónSaragossaSpain
  3. 3.CIBER Enfermedades Hepáticas y digestivas (CIBERehd)SaragossaSpain
  4. 4.Service of PathologyUniversity Hospital Lozano BlesaSaragossaSpain
  5. 5.University of ZaragozaSaragossaSpain
  6. 6.Service of GastroenterologyUniversity Hospital Lozano BlesaSaragossaSpain

Personalised recommendations