Combining Simvastatin with the Farnesyltransferase Inhibitor Tipifarnib Results in an Enhanced Cytotoxic Effect in a Subset of Primary CD34+ Acute Myeloid Leukemia Samples

Abstract

Purpose: To show whether the inhibitory effects of the cholesterol synthesis inhibitor simvastatin on human CD34 + acute myeloid leukemia (AML) cells can be further promoted by combining it with the farnesyltransferase inhibitor tipifarnib. Experimental Design: Normal CD34 + , AML CD34 + , and CD34 -sorted subfractions, and AML cell lines (TF-1and KG1A) were exposed to simvastatin and tipifarnib. Results: Both simvastatin and tipifarnib showed a cytotoxic effect on AML cell lines, which was additive when used in combination. In primary sorted CD34 + AML cells, a heterogeneous response pattern was observed upon treatment with simvastatin when analyzing cell survival. A group of normal (n = 12) and abnormal (n = 10) responders were identified within the AML CD34 + subfraction when compared with normal CD34 + cells. This distinction was not observed within the AML CD34 -cell fraction.When the CD34 + AML cells were exposed to simvastatin and tipifarnib, a significant enhanced inhibitory effect was shown exclusively in the normal AML responder group, whereas the AML CD34 -cell fractions all showed an enhanced inhibitory effect. The observed heterogeneity in AML responsiveness could not be explained by differences in effects on cholesterol metabolism genes or extracellular signal-regulated kinase phosphorylation in response to simvastatin and tipifarnib treatment. Conclusion:The results suggest that combined treatment with statins and farnesyltransferase inhibitors may be beneficial for a subset of AML patients that can be defined by studying the AML CD34 + fraction.

The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in malignancies: A comprehensive review

“…[77,78] Statins also negatively effect tumor cell adhesion, migration and chemotaxis, [79,80] and their synergism with multiple conventional anti-tumor agents has been described. [81][82][83][84] However, statins have also been implicated in interfering with the detection of CD20 and disrupting the anti-lymphoma activity of rituximab in lymphoma cell lines, leading to speculation regarding their true clinical potential. [85] In the Environmental Exposures and Lymphoid Neoplasms (EPILYMPH) study, which included 2362 patients with B-and T-cell lymphoma matched to 2206 controls, Fortuny et al [32] found a 39% decrease in the incidence of lymphomas among regular statin users, irrespective of treatment duration.…”

HMG-CoA reductase inhibitors as adjuvant treatment for hematologic malignancies: what is the current evidence?

“…As statins are capable of blocking both geranylgeranylation and farnesylation, it could be speculated that the combined use of tipifarnib and statins might have a stronger anti-leukemia effect. In this regard, Van der Weide et al investigated the effect of tipifarnib combined with simvastatin and in CD34+ AML cells [108]. A potentiated suppressive effect on cell survival was observed with simvastatin combined with tipifarnib when compared with either compound alone, which was characterized by an inhibition of cell cycle progression and enhanced apoptosis [108].…”

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

“…The increased sensitivity to this combination was more significant in HL60 compared to other leukemia cells tested whereas KG1 cells were more resistant with no signs of apoptosis. Heterogeneity in response was previously reported in a group of AML cell lines toward simvastatin or prenylation inhibitors [32] as well as in primary CD34 + AML cells cotreated with simvastatin and tipifarnib [33]. The differential sensitivity of AML cells toward simvastatin was attributed to the differences in interference with prenylation pathways [32].…”