The HMG-CoA reductase inhibitor lovastatin protects cells from the antineoplastic drugs doxorubicin and etoposide.
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.
Bardeleben
Renate V
RV
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, D-55131 Mainz, Germany.
Dunkern
Torsten
T
Kaina
Bernd
B
Fritz
Gerhard
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D002453:Cell Cycle / Q000187:drug effects; D020552:Comet Assay; D006224:Cricetinae; D004247:DNA / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology / Q000633:toxicity*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D005047:Etoposide; D004317:Doxorubicin; D004247:DNA; D008148:Lovastatin