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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.

SUBMITTER: Ahmed TA

PROVIDER: S-EPMC5628615 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Ahmed Tamer A TA Hayslip John J Leggas Markos M

Leukemia research 20140916 11

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 acc ...[more]

PMID: 25262449

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Project description:PURPOSE:To provide rationale for using phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathway inhibitors to treat rhabdomyosarcomas, a major cause of pediatric and adolescent cancer deaths. EXPERIMENTAL DESIGN:The prevalence of PI3K/MAPK pathway activation in rhabdomyosarcoma clinical samples was assessed using immunohistochemistry. Compensatory signaling and cross-talk between PI3K/MAPK pathways was determined in rhabdomyosarcoma cell lines following p110? short hairpin RNA-mediated depletion. Pharmacologic inhibition of reprogrammed signaling in stable p110? knockdown lines was used to determine the target-inhibition profile inducing maximal growth inhibition. The in vitro and in vivo efficacy of inhibitors of TORC1/2 (AZD8055), MEK (AZD6244), and P13K/mTOR (NVP-BEZ235) was evaluated alone and in pairwise combinations. RESULTS:PI3K pathway activation was seen in 82.5% rhabdomyosarcomas with coactivated MAPK in 36% and 46% of alveolar and embryonal subtypes, respectively. p110? knockdown in cell lines over the short and long term was associated with compensatory expression of other p110 isoforms, activation of the MAPK pathway, and cross-talk to reactivate the PI3K pathway. Combinations of PI3K pathway and MAP-ERK kinase (MEK) inhibitors synergistically inhibited cell growth in vitro. Treatment of RD cells with AZD8055 plus AZD6244 blocked reciprocal pathway activation, as evidenced by reduced AKT/ERK/S6 phosphorylation. In vivo, the synergistic effect on growth and changes in pharmacodynamic biomarkers was recapitulated using the AZD8055/AZD6244 combination but not NVP-BEZ235/AZD6244. Pharmacokinetic analysis provided evidence of drug-drug interaction with both combinations. CONCLUSIONS:Dual PI3K/MAPK pathway activation and compensatory signaling in both rhabdomyosarcoma subtypes predict a lack of clinical efficacy for single agents targeting either pathway, supporting a therapeutic strategy combining a TORC1/2 with a MEK inhibitor.

Dataset Information

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

Publications

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

Similar Datasets

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