HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data Buy All Versions of this Article: fj.08-117127v1 23/4/1127    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Google Scholar Google Scholar Articles by Rothmeier, A. S. Articles by Zahler, S. Search for Related Content PubMed PubMed Citation Articles by Rothmeier, A. S. Articles by Zahler, S.

Investigation of the marine compound spongistatin 1 links the inhibition of PKC translocation to nonmitotic effects of tubulin antagonism in angiogenesis

Andrea S. Rothmeier^*, Ivan Ischenko, Jos Joore, Dorota Garczarczyk, Robert Fürst^*, Christiane J. Bruns, Angelika M. Vollmar^* and Stefan Zahler^*,1

^* Department of Pharmacy, Center for Drug Research, and

Department of Surgery, Klinikum Großhadern, University of Munich, Munich, Germany;

Pepscan Systems BV, Lelystad, The Netherlands; and

Division of Medical Biochemistry, Innsbruck Medical University, Innsbruck, Austria

¹Correspondence: Department of Pharmacy, Center for Drug Research, University of Munich, Butenandtstr. 5-13, 81377 Munich, Germany. E-mail: stefan.zahler{at}cup.uni-muenchen.de

The aims of the study were to meet the demand of new tubulin antagonists with fewer side effects by characterizing the antiangiogenic properties of the experimental compound spongistatin 1, and to elucidate nonmitotic mechanisms by which tubulin antagonists inhibit angiogenesis. Although tubulin-inhibiting drugs and their antiangiogenic properties have been investigated for a long time, surprisingly little is known about their underlying mechanisms of action. Antiangiogenic effects of spongistatin 1 were investigated in endothelial cells in vitro, including functional cell-based assays, live-cell imaging, and a kinome array, and in the mouse cornea pocket assay in vivo. Spongistatin 1 inhibited angiogenesis at nanomolar concentrations (IC₅₀: cytotoxicity>50 nM, proliferation 100 pM, migration 1.0 nM, tube formation 1.0 nM, chemotaxis 1.0 nM, aortic ring sprouting 500 pM, neovascularization in vivo 10 µg/kg). Further, a kinome array and validating data showed that spongistatin 1 inhibits the phosphorylation activity of protein kinase C (PKC), an essential kinase in angiogenesis, and its translocation to the membrane. Thus, we conclude that PKC might be an important target for the antiangiogenic effects of tubulin antagonism. In addition, the data from the kinase array suggest that different tubulin antagonists might have individual intracellular actions.—Rothmeier, A. S., Ischenko, I., Joore, J., Garczarczyk, D., Fürst, R., Bruns, C. J., Vollmar, A. M., Zahler, S. Investigation of the marine compound spongistatin 1 links the inhibition of PKC translocation to nonmitotic effects of tubulin antagonism in angiogenesis.

Key Words: angiogenesis • microtubules • chemotaxis • protein kinase C