Nature Medicine
5, 1418 - 1423 (1999)
doi:10.1038/70995
Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight
into mechanisms and implications for cancer growth and ulcer healingMichael K. Jones1, Hongtao Wang3, Brigitta M. Peskar5, Ellis Levin1, 3, Rabiha M. Itani1, I. James Sarfeh2, 4
& Andrzej S. Tarnawski1, 31
Department of Medicine, Veterans Affairs Medical Center
, 5901 East Seventh Street, Long Beach,
California 90822, USA
2
Department of Surgery, Veterans Affairs Medical Center
, 5901 East Seventh Street, Long Beach,
California 90822, USA
3
Department of Medicine, University of California,
Irvine, California 92697, USA
4
Department of Surgery, University of California,
Irvine, California 92697, USA
5
Department of Experimental Clinical Medicine, Ruhr-University
of Bochum, D-44780 Bochum, Germany
Correspondence should be addressed to Andrzej S. Tarnawski astarnaw@uci.eduAngiogenesis, 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.
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