title: Simvastatin interacts synergistically with tipifarnib to induce apoptosis in leukemia cells through the disruption of RAS membrane localization and ERK pathway inhibition.
abstract: Tipifarnib, a farnesyltransferase inhibitor (FTI), was initially designed to disrupt RAS farnesylation and membrane localization necessary for RAS function. However, alternative geranylgeranylation has been postulated as an escape mechanism by which RAS bypasses the effect of FTI treatment. In this study, we demonstrate that simvastatin, an HMG-CoA reductase inhibitor, augments the cytotoxic effect of tipifarnib by blocking the alternative geranylgeranylation of RAS. Notably, this effect was accompanied by disruption of RAS membrane localization and ERK downregulation. In addition, the apoptotic effect of this combination was associated with downregulation of the antiapoptotic Mcl-1 protein and activation of the caspase cascade. These findings demonstrate that combining tipifarnib and simvastatin was successful in targeting RAS/ERK signaling and inducing apoptosis in leukemia cells. Both simvastatin and tipifarnib were used at clinically achievable doses, which make the combination promising for future clinical studies.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Tamer A
authors.initials: TA
authors.lastname: Ahmed
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Division of Hematology and Blood and Marrow Transplantation, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hayslip
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: mark.leggas@uky.edu.
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007938:Leukemia / Q000201:enzymology / Q000473:pathology*; D015363:Quinolones / Q000494:pharmacology*; D019821:Simvastatin / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015363:Quinolones; D019821:Simvastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; C402769:tipifarnib
keywords: RAS/ERK, Leukemia; Simvastatin; Tipifarnib