Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight into mechanisms and implications for cancer growth and ulcer healing


Angiogenesis, the formation of new capillary blood vessels, is essential not only for the growth and metastasis of solid tumors, but also for wound and ulcer healing, because without the restoration of blood flow, oxygen and nutrients cannot be delivered to the healing site1,2. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used drugs for pain, arthritis, cardiovascular diseases and, more recently, the prevention of colon cancer and Alzheimer disease3,4,5,6,7. However, NSAIDs produce gastroduodenal ulcers in about 25% of users (often with bleeding and/or perforations) and delay ulcer healing8,9, presumably by blocking prostaglandin synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both selective and nonselective NSAIDs inhibit angiogenesis through direct effects on endothelial cells. We also show that this action involves inhibition of mitogen-activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear translocation, is independent of protein kinase C and has prostaglandin-dependent and prostaglandin-independent components. Finally, we show that both COX-1 and COX-2 are important for the regulation of angiogenesis. These findings challenge the premise that selective COX-2 inhibitors will not affect the gastrointestinal tract and ulcer/wound healing.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: In vitro angiogenesis.
Figure 2: Effects of indomethacin and NS-398 on ERK2 activity in rat primary endothelial and HMVECs.
Figure 3: Effects of indomethacin and NS-398 on ERK2 activity and ERK2 nuclear translocation in rat primary endothelial cells.
Figure 4: Serum-starved rat primary endothelial cells or serum-deprived HMVECs were treated for 16 h with either vehicle (controls), 0.


  1. 1

    Folkman, J. & Shing, Y. Angiogenesis. J. Biol. Chem. 267, 10931–10934 (1992).

    CAS  PubMed  Google Scholar 

  2. 2

    Tarnawski, A. et al. in Mechanisms of Peptic Ulcer Healing/Falk Symposium 59. (eds. Halter, F., Garner, A. & Tytgat, G.N.J.) 165– 171 (Kluwer Academic, London, 1991).

    Google Scholar 

  3. 3

    Schuna, A.A. Update on treatment of rheumatoid arthritis. J. Am. Pharm. Assoc. (Wash.) 38, 728–735 (1998).

    CAS  Article  Google Scholar 

  4. 4

    Goodnight, S.H. Aspirin therapy for cardiovascular disease. Curr. Opin. Hematol. 3, 355–360 (1996).

    CAS  Article  Google Scholar 

  5. 5

    Sheng, H. et al. Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J. Clin. Invest. 99, 2254–2259 (1997).

    CAS  Article  Google Scholar 

  6. 6

    Shiff, S.J. & Rigas, B. Nonsteroidal anti-inflammatory drugs and colorectal cancer: evolving concepts of their chemopreventive actions. Gastroenterology 113, 1992– 1998 (1997).

    CAS  Article  Google Scholar 

  7. 7

    Sloane, P.D. Advances in treatment of Alzheimer's disease. Am Fam. Physician 58, 1577–1586 (1998).

    CAS  PubMed  Google Scholar 

  8. 8

    Fries, J.F. NSAID gastropathy: the second most deadly rheumatic disease? Epidemiology and risk appraisal. J. Rheumatol. 18, 6– 10 (1991).

    Google Scholar 

  9. 9

    Shea-Donohue, T., Steel, L., Montcalm-Mazzilli, E. & Dubois, A. Aspirin-induced changes in gastric function: role of endogenous prostaglandins and mucosal damage. Gastroenterology 98, 284–292 (1990).

    CAS  Article  Google Scholar 

  10. 10

    Smith, W. & Marnett, L. Prostaglandin endoperoxide synthase: structure and catalysis. Biochem. Biophys. Acta. 1083 , 1–17 (1991).

    CAS  Article  Google Scholar 

  11. 11

    DeWitt, D.L., Meade, E.A. & Smith, W.L. PGH synthase isoenzyme selectivity: the potential for safer non-steroidal drugs. Am. J. Med. 95, 40S–44S (1993).

    CAS  Article  Google Scholar 

  12. 12

    Florkiewicz, R.Z. & Sommer, A. Human basic fibroblast growth factor gene encodes four polypeptides: three initiate translation from non-AUG codons. Proc. Natl. Acad. Sci. USA 86, 3978–3981 (1989).

    CAS  Article  Google Scholar 

  13. 13

    Nicosia, R.F., Lin, Y.J., Hazelton, D. & Qian, X. Endogenous regulation of angiogenesis in the rat aorta model: role of vascular endothelial growth factor. Am. J. Pathol. 151, 1379– 1386 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Jones, M.K., Sarfeh, I.J. & Tarnawski, A.S. Induction of in vitro angiogenesis in the endothelial-derived cell line EA hy926, by ethanol is mediated through PKC and MAPK. Biochem. Biophys. Res. Comm. 249, 118– 123 (1998).

    CAS  Article  Google Scholar 

  15. 15

    Tsujii, M. et al. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93, 705–716 (1998).

    CAS  Article  Google Scholar 

  16. 16

    Skopinska-Rozewska, E. et al. Inhibition of angiogenesis by sulindac and its sulfone metabolite (FGN-1): a potential mechanism for their antineoplastic properties. Int. J. Tissue React. 20, 85–89 (1998).

    CAS  PubMed  Google Scholar 

  17. 17

    Futaki, N. et al. NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro. Prostaglandins 47, 55– 59 (1994).

    CAS  Article  Google Scholar 

  18. 18

    Masferrer, J.L. et al. Selective inhibition of inducible cyclooxygenase 2 in vitro is antiinflammatory and nonulcerogenic. Proc. Natl. Acad. Sci. USA 91, 3228–3232 (1994).

    CAS  Article  Google Scholar 

  19. 19

    McCarthy, D.M. Mechanisms of mucosal injury and healing: the role of non-steroidal-anti-inflammatory drugs. Scand. J. Gastroenterol. 208, 9– 16 (1995).

    Google Scholar 

  20. 20

    Tarnawski, A. et al. Angiogenic response of gastric mucosa to ethanol injury is abolished by indomethacin. Gastroenterology 96, A505 (1989).

    Google Scholar 

  21. 21

    Tarnawski, A. et al. in Mechanism of Injury, Protection and Repair of the Upper Gastrointestinal Tract (eds. Garner, A., & O'Brien, P.E.) 521–531 (J. Willey & Sons, Chichester, 1991).

    Google Scholar 

  22. 22

    Schmassmann, A. et al. Effects of inhibition of prostaglandin endoperoxide synthase-2 in chronic gastro-intestinal ulcer models in rats. Br. J. Pharmacol. 123, 795–804 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Scharschmidt, L.A. & Dunn, M.J. Prostaglandin synthesis by rat glomerular mesangial cells in culture. Effects of angiotensin II and arginine vasopressin. J. Clin. Invest. 71, 1756–1764 (1983).

    CAS  Article  Google Scholar 

  24. 24

    Pai, R., Ohta, M., Itani, R.M., Sarfeh, I.J. & Tarnawski, A.S. Induction of mitogen-activated protein kinase signal transduction pathway during gastric ulcer healing in rats. Gastroenterology 114, 706–713 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Peskar, B.A., Steffens, C. & Peskar, B.M. in Radioimmunoassay of Drugs and Hormones in Cardiovascular Medicine (eds. Albertini, A., DaPrada, M. & Peskar, B.A.) 239–250 (Elsevier/North Holland Biomedical, Amsterdam, New York, Oxford, 1979).

    Google Scholar 

Download references


The authors thank D.T. Vo, B. Gretzer and M. Tomikawa for technical assistance, and R. Pai for discussions. This work was supported by the Medical Research Service of the Department of Veterans Affairs, Merit Review (A.S.T.) and Research Enhancement Award Programs.

Author information



Corresponding author

Correspondence to Andrzej S. Tarnawski.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jones, M., Wang, H., Peskar, B. et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight into mechanisms and implications for cancer growth and ulcer healing. Nat Med 5, 1418–1423 (1999).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing