This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Saha, D. Articles by Freeman, M. L. Search for Related Content PubMed PubMed Citation Articles by Saha, D. Articles by Freeman, M. L.

The Antiangiogenic Agent SU5416 Down-Regulates Phorbol Ester-Mediated Induction of Cyclooxygenase 2 Expression by Inhibiting Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activity¹

Departments of Radiation Oncology [D. S., K. R. S., C. C., H. C., M. L. F.] and Clinical Pharmacology [J. D. M.], Vanderbilt University Medical Center, Vanderbilt University Ingram Cancer Center, Nashville, Tennessee 37232

Increased expression of cyclooxygenase (COX) 2 and the production of PGs appear to provide a survival advantage to transformed cells through the inhibition of apoptosis, increased attachment to extracellular matrix, increased invasiveness and the stimulation of angiogenesis. The purpose of this study was to determine whether an angiogenic antagonist, SU5416, could inhibit endogenous and phorbol 12-myristate 13-acetate (PMA)-mediated induction of COX-2 expression. SU5416 (5 µM) inhibited endogenous as well as PMA-mediated induction of COX-2 expression when analyzed by immunoblot and Northern blot analysis. However, COX-1 expression remained unchanged under similar conditions. PMA is a potent inducer of reactive oxygen species that can play an important role during the induction of COX-2 expression. Our results demonstrated that PMA-mediated induction of COX-2 expression was found to be dependent on NADPH oxidase activity. An inhibitor of NADPH oxidase (diphenyleneiodonium chloride) blocked the PMA-mediated induction of COX-2 expression. The oxidase complex exhibited a temporal pattern of activation after exposure to PMA in which maximum activation was observed at 30 min after the addition of PMA. Activation of NADPH oxidase was also inhibited by SU5416, whereas an inhibitor of epidermal growth factor receptor signaling was unable to prevent the PMA-mediated induction of NADPH oxidase activity. When we blocked the PMA-mediated production of reactive oxygen species by blocking NADPH oxidase with SU5416, COX-2 expression and PGE₂ synthesis were also inhibited. Our results suggest that inhibition of NADPH oxidase activity, blocking of COX-2 expression, and PGE₂ synthesis may represent novel targets for SU5416.

This article has been cited by other articles:

				W. Koh, R. D. Mahan, and G. E. Davis Cdc42- and Rac1-mediated endothelial lumen formation requires Pak2, Pak4 and Par3, and PKC-dependent signaling J. Cell Sci., April 1, 2008; 121(7): 989 - 1001. [Abstract] [Full Text] [PDF]

				C. R. Amura, K. S. Brodsky, R. Groff, V. H. Gattone, N. F. Voelkel, and R. B. Doctor VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/-) mice Am J Physiol Cell Physiol, July 1, 2007; 293(1): C419 - C428. [Abstract] [Full Text] [PDF]

				E. Lee, M.-K. Choi, Y.-J. Lee, J.-L. Ku, K.-H. Kim, J.-S. Choi, and S.-J. Lim Alpha-tocopheryl succinate, in contrast to alpha-tocopherol and alpha-tocopheryl acetate, inhibits prostaglandin E2 production in human lung epithelial cells Carcinogenesis, November 1, 2006; 27(11): 2308 - 2315. [Abstract] [Full Text] [PDF]

				P. Mukhopadhyay, M. A. Ali, A. Nandi, P. Carreon, H. Choy, and D. Saha The Cyclin-Dependent Kinase 2 Inhibitor Down-regulates Interleukin-1{beta}-Mediated Induction of Cyclooxygenase-2 Expression in Human Lung Carcinoma Cells Cancer Res., February 1, 2006; 66(3): 1758 - 1766. [Abstract] [Full Text] [PDF]