Simvastatin interacts synergistically with tipifarnib to induce apoptosis in leukemia cells through the disruption of RAS membrane localization and ERK pathway inhibition

Tamer A. Ahmed, John Hayslip, Markos Leggas

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Pages (from-to)1350-1357
Number of pages8
JournalLeukemia Research
Volume38
Issue number11
DOIs
StatePublished - Nov 1 2014

Bibliographical note

Publisher Copyright:
© 2014 Elsevier Ltd.

Keywords

  • RAS/ERK, Leukemia
  • Simvastatin
  • Tipifarnib

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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