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: Davide Staedler, Catherine Chapuis-Bernasconi, Henrietta Dehmlow, Holger Fischer, Lucienne Juillerat-Jeanneret, Johannes D Aebi
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 11 Pg. 4990-5002 (Jun 14 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22533316 (Publication Type: Journal Article)

Chemical References

• Alkynes
• Angiogenesis Inhibitors
• Anticholesteremic Agents
• Antineoplastic Agents
• Carbamates
• Cyclohexanes
• Heptanoic Acids
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Pyrroles
• Atorvastatin
• Intramolecular Transferases
• lanosterol synthase

Topics

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