The HMG-CoA reductase inhibitor lovastatin protects cells from the antineoplastic drugs doxorubicin and etoposide

  • Authors:
    • Renate V. Bardeleben
    • Torsten Dunkern
    • Bernd Kaina
    • Gerhard Fritz
  • View Affiliations

  • Published online on: October 1, 2002     https://doi.org/10.3892/ijmm.10.4.473
  • Pages: 473-479
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Abstract

Ras-homologous GTPases are involved in the regulation of genotoxic stress-induced gene expression and cell death. Since they need C-terminal isoprenylation for correct intracellular localization and function, we investigated whether depletion of cells from isopren precursor moieties using the HMG-CoA reductase inhibitor lovastatin affects cellular sensitivity to DNA damaging drugs. Here we show that lovastatin renders cells highly resistant to the tumor-therapeutic compound doxorubicin. Desensitization by lovastatin was reverted by co-treatment with GGPP indicating that inhibition of protein geranylgeranylation is involved in acquired doxorubicin resistance. Lovastatin does not influence cellular sensitivity to DNA damaging compounds such as cisplatin, methyl methanesulfonate and ionizing radiation. The frequency of apoptotic cell death induced by doxorubicin was not affected by lovastatin as shown by both annexin V and DNA fragmentation assay. However, lovastatin releases cells from doxorubicin induced G2 blockage. Furthermore, lovastatin protects cells from doxorubicin-induced DNA strand breakage without affecting drug uptake or the expression of multidrug resistance protein (mdr-1). Since lovastatin confers cross-resistance to the topoisomerase II specific inhibitor etoposide, we suggest desensitization by the statin to be related to topoisomerase II function. The finding that lovastatin renders cells resistant to doxorubicin and etoposide by reducing their genotoxic and cytotoxic effects might have clinical implications for cancer therapy.

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October 2002
Volume 10 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Bardeleben RV, Dunkern T, Kaina B and Fritz G: The HMG-CoA reductase inhibitor lovastatin protects cells from the antineoplastic drugs doxorubicin and etoposide. Int J Mol Med 10: 473-479, 2002.
APA
Bardeleben, R.V., Dunkern, T., Kaina, B., & Fritz, G. (2002). The HMG-CoA reductase inhibitor lovastatin protects cells from the antineoplastic drugs doxorubicin and etoposide. International Journal of Molecular Medicine, 10, 473-479. https://doi.org/10.3892/ijmm.10.4.473
MLA
Bardeleben, R. V., Dunkern, T., Kaina, B., Fritz, G."The HMG-CoA reductase inhibitor lovastatin protects cells from the antineoplastic drugs doxorubicin and etoposide". International Journal of Molecular Medicine 10.4 (2002): 473-479.
Chicago
Bardeleben, R. V., Dunkern, T., Kaina, B., Fritz, G."The HMG-CoA reductase inhibitor lovastatin protects cells from the antineoplastic drugs doxorubicin and etoposide". International Journal of Molecular Medicine 10, no. 4 (2002): 473-479. https://doi.org/10.3892/ijmm.10.4.473