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Heterogeneity in simvastatin-induced cytotoxicity in AML is caused by differences in Ras-isoprenylation

Leukemia volume 26, pages 845–848 (2012)Cite this article

Different mechanisms have been identified that protect acute myeloid leukemia (AML) cells against the cytotoxic actions of chemotherapy, including dysregulation of cellular cholesterol homeostasis.1 So far, it has been shown that in vitro AML cells display an enhanced cholesterol metabolism.2 Moreover, AML cells increase their cholesterol contents upon exposure to chemotherapeutic drugs, which may render them less susceptible to the cytotoxic actions of these drugs.1 Therefore, interfering with the cholesterol metabolism by using statins to suppress cholesterol synthesis has been proposed as a method to improve antileukemic treatment strategies.3

Statins (for example, simvastatin) are widely used plasma cholesterol-lowering drugs that inhibit cholesterol synthesis at the level of HMG-CoA reductase (HMG-CoAR) by blocking the conversion of HMG-CoA to mevalonate. Mevalonate is also the precursor of isoprenoids such as farnesyldiphosphate (FPP) and geranylgeranyldiphosphate (GGPP). Isoprenylation, catalyzed by farnesyltransferase or geranylgeranyltransferase, is required for the attachment of small GTPases (for example, Rho, Ras) to the plasma membrane and their subsequent participation in signal transduction pathways that regulate growth and survival. Statins induce cell death in various human AML cell lines, as well as in primary human AML cells in vitro.1, 4 Different mechanisms of action have been proposed for simvastatin-mediated cell death, including the direct consequences of suppressed cholesterol synthesis and inhibition of isoprenylation and thereby the actions of signaling molecules such as Ras.1, 5 Ras is frequently activated in AML cells by mutations, or because of the autocrine or paracrine production of growth factors.6 We recently observed a heterogeneity in cytotoxicity among primary human AML cells upon in vitro treatment with simvastatin.4 These results suggest that only a subset of AML patients may benefit from statin treatment. In order to be able to predict which patients may benefit from statin treatment, we investigated whether the differences in simvastatin-induced cytotoxicity are confined to differential effects on the cholesterol synthesis route or on the isoprenylation route.

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Acknowledgements

This study was supported by a grant of the Dutch Cancer Society (RUG 2006-3580).

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Authors and Affiliations

  1. Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    K van der Weide, P M Korthuis & E Vellenga

  2. Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    K van der Weide & E G E de Vries

  3. Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    F Kuipers

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  1. K van der Weide
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Correspondence to E Vellenga.

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van der Weide, K., Korthuis, P., Kuipers, F. et al. Heterogeneity in simvastatin-induced cytotoxicity in AML is caused by differences in Ras-isoprenylation. Leukemia 26, 845–848 (2012). https://doi.org/10.1038/leu.2011.259

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