title: Endothelin-converting enzyme-1 inhibition and growth of human glioblastoma cells.
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.
authors.affiliation: University Institute of Pathology, University of Lausanne, Bugnon 25, CH1011 Lausanne, Switzerland.
authors.forename: Yann
authors.initials: Y
authors.lastname: Berger
authors.forename: Henrietta
authors.initials: H
authors.lastname: Dehmlow
authors.forename: Denise
authors.initials: D
authors.lastname: Blum-Kaelin
authors.forename: Eric A
authors.initials: EA
authors.lastname: Kitas
authors.forename: Bernd-Michael
authors.initials: BM
authors.lastname: Löffler
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Aebi
authors.forename: Lucienne
authors.initials: L
authors.lastname: Juillerat-Jeanneret
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016543:Central Nervous System Neoplasms; D004354:Drug Screening Assays, Antitumor; D019332:Endothelin-1 / Q000494:pharmacology; D000072396:Endothelin-Converting Enzymes; D005909:Glioblastoma; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry; D008666:Metalloendopeptidases; D011392:Proline / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D019332:Endothelin-1; D006834:Hydrazines; D011743:Pyrimidines; D011759:Pyrrolidines; D013438:Sulfhydryl Compounds; D011392:Proline; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes