Endothelin-converting enzyme-1 inhibition and growth of human glioblastoma cells.

Basic Information

ID: ALA1144347

Journal: J Med Chem

Title: Endothelin-converting enzyme-1 inhibition and growth of human glioblastoma cells.

Authors: Berger Y, Dehmlow H, Blum-Kaelin D, Kitas EA, Löffler BM, Aebi JD, Juillerat-Jeanneret L.

Abstract: 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 1(a)(-)(d) (ECE-1(a)(-)(d); EC 3.4.24.71) 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 3.4.24.11) and angiotensin-converting enzyme (ACE; EC 3.4.15.1), 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.

CiteXplore: 15658862

DOI: 10.1021/jm040857x

Patent ID: ┄