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

• Published in: Journal of medicinal chemistry Vol. 48; no. 2; pp. 483 - 498
• Main Authors: Berger, Yann, Dehmlow, Henrietta, Blum-Kaelin, Denise, Kitas, Eric A, Löffler, Bernd-Michael, Aebi, Johannes D, Juillerat-Jeanneret, Lucienne
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 27-01-2005
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Carbamates - chemical synthesis; Carbamates - chemistry; Cell Line, Tumor; Cell Proliferation - drug effects; Central Nervous System Neoplasms; Drug Screening Assays, Antitumor; Endothelin-1 - pharmacology; Endothelin-Converting Enzymes; Glioblastoma; Humans; Hydrazines - chemical synthesis; Hydrazines - chemistry; Metalloendopeptidases; Proline - analogs & derivatives; Proline - chemical synthesis; Proline - chemistry; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Structure-Activity Relationship; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040857x

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 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.