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.
MeSH terms
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Alkynes / chemical synthesis
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Alkynes / chemistry
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Alkynes / pharmacology*
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Angiogenesis Inhibitors / chemical synthesis
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology
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Animals
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Anticholesteremic Agents / chemical synthesis
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Anticholesteremic Agents / chemistry
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Anticholesteremic Agents / pharmacology*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Atorvastatin
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Brain / blood supply
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Carbamates / chemical synthesis
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Carbamates / chemistry
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Carbamates / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cricetinae
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Cyclohexanes / chemical synthesis
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Cyclohexanes / chemistry
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Cyclohexanes / pharmacology*
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Drug Screening Assays, Antitumor
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Drug Synergism
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Heptanoic Acids / pharmacology*
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
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Intramolecular Transferases / antagonists & inhibitors*
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Microsomes, Liver / enzymology
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Neovascularization, Pathologic / pathology
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Pyrroles / pharmacology*
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Structure-Activity Relationship
Substances
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Alkynes
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Angiogenesis Inhibitors
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Anticholesteremic Agents
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Antineoplastic Agents
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Carbamates
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Cyclohexanes
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Heptanoic Acids
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Pyrroles
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Atorvastatin
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Intramolecular Transferases
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lanosterol synthase