Lovastatin protects human endothelial cells from the genotoxic and cytotoxic effects of the anticancer drugs doxorubicin and etoposide.
OBJECTIVE
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are frequently used lipid-lowering drugs. Moreover, they exert pleiotropic effects on cellular stress responses and death. Here, we analysed whether lovastatin affects the sensitivity of primary human endothelial cells (HUVEC) to the anticancer drug doxorubicin.


METHODS
We investigated whether pretreatment of HUVEC with low dose of lovastatin influences the cellular sensitivity to doxorubicin. To this end, cell viability, proliferation and apoptosis as well as DNA damage-triggered stress response were analysed.


RESULTS
Lovastatin reduced the cytotoxic potency of doxorubicin in HUVEC. Lovastatin attenuated the doxorubicin-induced increase in p53 as well as activation of checkpoint kinase (Chk-1) and stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK). Acquired doxorubicin resistance was independent of alterations in doxorubicin efflux and cell cycle progression. Also, doxorubicin-triggered production of reactive oxygen species (ROS) and formation of oxidative DNA lesions remained unaffected by lovastatin. However, lovastatin impaired DNA strand break formation induced by doxorubicin. Notably, lovastatin also conferred cross-resistance to the cytotoxic and genotoxic effects of etoposide, indicating that lovastatin shields topoisomerase II against poisons.


CONCLUSIONS
Based on these data, we suggest that lovastatin-mediated resistance to topoisomerase II inhibitors is due to a reduction in DNA damage and, hence, it attenuates stress responses leading to cell death that are triggered by DNA damage. Therefore, lovastatin might be useful clinically for alleviating side-effects of anticancer therapies that include topoisomerase II inhibitors.
Damrot
J
J
Department of Toxicology, University of Mainz, Mainz, Germany.
Nübel
T
T
Epe
B
B
Roos
W P
WP
Kaina
B
B
Fritz
G
G
D000903:Antibiotics, Antineoplastic / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D016587:Antimutagenic Agents; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004317:Doxorubicin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity*; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects*; D005047:Etoposide / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D005347:Fibroblasts / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059005:Topoisomerase II Inhibitors
D000903:Antibiotics, Antineoplastic; D016587:Antimutagenic Agents; D000972:Antineoplastic Agents, Phytogenic; D005456:Fluorescent Dyes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004317:Doxorubicin; D008148:Lovastatin; D016650:Fluorescein-5-isothiocyanate