The Mevalonate/Isoprenoid Pathway Inhibitor Apomine (SR-45023A) Is Antiproliferative and Induces Apoptosis Similar to Farnesol

• Published in: Biochemical and biophysical research communications 2000-04, Vol.270 (1), p.240-246
• Main Authors: Flach, Jean, Antoni, Isabelle, Villemin, Pascal, Bentzen, Craig L., Niesor, Eric J.
• Format: Article
• Language: English
• Subjects: Anticholesteremic Agents - pharmacology; Antineoplastic Agents - pharmacology; Apomine; Apoptosis; caspase-3; Cell Division - drug effects; cholesterol; Diphosphonates - pharmacology; Dose-Response Relationship, Drug; farnesol; Farnesol - pharmacology; Humans; Hydroxycholesterols - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Mevalonic Acid - metabolism; Molecular Mimicry; Simvastatin - pharmacology; Terpenes - metabolism; Tumor Cells, Cultured
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.2000.2421

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 IC50 values ranging from 5 to 14 μM. 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 (IC50 = 14 μM), simvastatin (IC50 = 3 μM), farnesol (IC50 = 60 μM), and 25-hydroxycholesterol (IC50 = 2 μM) 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 IC50 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.