Article: article from journal or magazin.
Endothelin-converting enzyme-1 inhibition and growth of human glioblastoma cells
Journal of Medicinal Chemistry
PT - Journal Article PT - Research Support, Non-U.S. Gov't
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 188.8.131.52) 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 184.108.40.206) and angiotensin-converting enzyme (ACE; EC 220.127.116.11), 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
Antineoplastic Agents/chemical synthesis/chemistry/pharmacology/Aspartic Endopeptidases/antagonists & inhibitors/Carbamates/Cell Line,Tumor/Cell Proliferation/drug effects/Central Nervous System Neoplasms/Drug Screening Assays,Antitumor/Endothelin-1/Glioblastoma/Humans/Hydrazines/Metalloendopeptidases/Proline/analogs & derivatives/Pyrimidines/Pyrrolidines/Structure-Activity Relationship/Sulfhydryl Compounds
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