TY - JOUR
T1 - Simvastatin interacts synergistically with tipifarnib to induce apoptosis in leukemia cells through the disruption of RAS membrane localization and ERK pathway inhibition
AU - Ahmed, Tamer A.
AU - Hayslip, John
AU - Leggas, Markos
N1 - Publisher Copyright:
© 2014 Elsevier Ltd.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - 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.
AB - 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.
KW - RAS/ERK, Leukemia
KW - Simvastatin
KW - Tipifarnib
UR - http://www.scopus.com/inward/record.url?scp=84910080489&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84910080489&partnerID=8YFLogxK
U2 - 10.1016/j.leukres.2014.09.002
DO - 10.1016/j.leukres.2014.09.002
M3 - Article
C2 - 25262449
AN - SCOPUS:84910080489
SN - 0145-2126
VL - 38
SP - 1350
EP - 1357
JO - Leukemia Research
JF - Leukemia Research
IS - 11
ER -