title: Cytotoxic effects of combination of oxidosqualene cyclase inhibitors with atorvastatin in human cancer cells.
abstract: Ten oxidosqualene cyclase inhibitors with high efficacy as cholesterol-lowering agents and of different chemical structure classes were evaluated as potential anticancer agents against human cancer cells from various tissue origins and nontumoral human-brain-derived endothelial cells. Inhibition of cancer cell growth was demonstrated at micromolar concentrations, comparable to the concentrations of statins necessary for antitumor effect. Human glioblastoma cells were among the most sensitive cells. These compounds were also able to decrease the proliferation of angiogenic brain-derived endothelial cells, as a model of tumor-induced neovasculation. Additive effects in human glioblastoma cells were also demonstrated for oxidosqualene cyclase inhibitors in combination with atorvastatin while maintaining selectivity against endothelial cells. Thus, not only statins targeting the 3-hydroxy-3-methylglutaryl coenzyme A reductase but also inhibitors of oxidosqualene cyclase decrease tumor growth, suggesting new therapeutic opportunities of combined anti-cholesterol agents for dual treatment of glioblastoma.
authors.affiliation: Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne (UNIL), CH-1011 Lausanne, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Staedler
authors.forename: Catherine
authors.initials: C
authors.lastname: Chapuis-Bernasconi
authors.forename: Henrietta
authors.initials: H
authors.lastname: Dehmlow
authors.forename: Holger
authors.initials: H
authors.lastname: Fischer
authors.forename: Lucienne
authors.initials: L
authors.lastname: Juillerat-Jeanneret
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Aebi
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000069059:Atorvastatin; D001921:Brain / Q000098:blood supply; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D008862:Microsomes, Liver / Q000201:enzymology; D009389:Neovascularization, Pathologic / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000480:Alkynes; D020533:Angiogenesis Inhibitors; D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D002219:Carbamates; D003510:Cyclohexanes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D019751:Intramolecular Transferases; C021924:lanosterol synthase