title: The mevalonate/isoprenoid pathway inhibitor apomine (SR-45023A) is antiproliferative and induces apoptosis similar to farnesol.
abstract: Apomine (SR-45023A) is a new antineoplastic compound which is currently in clinical trials and representative of the family of cholesterol synthesis inhibitors 1,1-bisphosphonate esters. Apomine inhibits growth of a wide variety of tumor cell lines with IC(50) values ranging from 5 to 14 microM. The antiproliferative activity of apomine was studied in comparison with that of other inhibitors of the mevalonate/isoprenoid pathway of cholesterol synthesis, simvastatin, farnesol, and 25-hydroxycholesterol. All these compounds inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity. Apomine (IC(50) = 14 microM), simvastatin (IC(50) = 3 microM), farnesol (IC(50) = 60 microM), and 25-hydroxycholesterol (IC(50) = 2 microM) inhibited HL60 cell growth. Growth inhibition due to simvastatin was reverted by mevalonate, whereas the antiproliferative activity of apomine, farnesol, and 25-hydroxycholesterol was not. Apomine triggered apoptosis in HL60 cells in less than 2 h. Apomine and farnesol induced caspase-3 activity at concentrations similar to their IC(50) values for cell proliferation, whereas a 10-fold excess of simvastatin was necessary to trigger apoptosis compared to its potency on proliferation. Caspase-3 activity was not induced by 25-hydroxycholesterol. The overall similar profile on mevalonate synthesis inhibition, cell growth inhibition, and apoptosis suggests that apomine acts as a synthetic mimetic of farnesol.
authors.affiliation: Symphar, 243 rte des Fayards, Versoix/Geneva, 1290, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Flach
authors.forename: I
authors.initials: I
authors.lastname: Antoni
authors.forename: P
authors.initials: P
authors.lastname: Villemin
authors.forename: C L
authors.initials: CL
authors.lastname: Bentzen
authors.forename: E J
authors.initials: EJ
authors.lastname: Niesor
mesh_terms: D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005204:Farnesol / Q000494:pharmacology*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism; D018716:Molecular Mimicry; D019821:Simvastatin / Q000494:pharmacology; D013729:Terpenes / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D004164:Diphosphonates; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013729:Terpenes; C407151:apomine; D005204:Farnesol; C007997:25-hydroxycholesterol; D019821:Simvastatin; D008798:Mevalonic Acid