期刊
LEUKEMIA RESEARCH
卷 38, 期 11, 页码 1350-1357出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.leukres.2014.09.002
关键词
Tipifarnib; Simvastatin; RAS/ERK, Leukemia
资金
- Office of the Vice President for Research
- Markey Cancer Center
- NCI Center Core Support Grant [P30 CA177558]
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. (C) 2014 Elsevier Ltd. All rights reserved.
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