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Endothelin-Converting Enzyme-1 Inhibition and Growth of Human Glioblastoma Cells

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journal contribution
posted on 27.01.2005 by Yann Berger, Henrietta Dehmlow, Denise Blum-Kaelin, Eric A. Kitas, Bernd-Michael Löffler, Johannes D. Aebi, Lucienne Juillerat-Jeanneret
Endothelin-1 (ET-1) is mitogenic and/or antiapoptotic in human cancers, and antagonists to ET-1 receptors are under evaluation for cancer treatment. Inhibition of ET-1 activation by the endothelin-converting enzymes 1a-d (ECE-1a-d; EC represents another approach to block the ET-1 effect in cancer. To evaluate this potential, we synthesized and characterized a series of low nanomolar nonpeptidic thiol-containing ECE-1 inhibitors, and evaluated their effect, as well as the effect of inhibitors for the related metalloproteases neprilysin (NEP; EC and angiotensin-converting enzyme (ACE; EC, on human glioblastoma cell growth. Only ECE-1 inhibitors inhibited DNA synthesis by human glioblastoma cells. Exogenous addition of ET-1 or bigET-1 to glioblastoma cells did not counterbalance the growth inhibition elicited by ECE-1 inhibitors, suggesting that ECE-1 inhibitors block the proliferation of human glioblastoma cells most likely via a mechanism not involving extracellular production of ET-1. This class of molecules may thus represent novel therapeutic agents for the potential treatment of human cancer.