title: Lovastatin prevents cisplatin-induced activation of pro-apoptotic DNA damage response (DDR) of renal tubular epithelial cells.
abstract: The platinating agent cisplatin (CisPt) is commonly used in the therapy of various types of solid tumors. The anticancer efficacy of CisPt largely depends on the formation of bivalent DNA intrastrand crosslinks, which stimulate mechanisms of the DNA damage response (DDR), thereby triggering checkpoint activation, gene expression and cell death. The clinically most relevant adverse effect associated with CisPt treatment is nephrotoxicity that results from damage to renal tubular epithelial cells. Here, we addressed the question whether the HMG-CoA-reductase inhibitor lovastatin affects the DDR of renal cells by employing rat renal proximal tubular epithelial (NRK-52E) cells as in vitro model. The data show that lovastatin has extensive inhibitory effects on CisPt-stimulated DDR of NRK-52E cells as reflected on the levels of phosphorylated ATM, Chk1, Chk2, p53 and Kap1. Mitigation of CisPt-induced DDR by lovastatin was independent of the formation of DNA damage as demonstrated by (i) the analysis of Pt-(GpG) intrastrand crosslink formation by Southwestern blot analyses and (ii) the generation of DNA strand breaks as analyzed on the level of nuclear γH2AX foci and employing the alkaline comet assay. Lovastatin protected NRK-52E cells from the cytotoxicity of high CisPt doses as shown by measuring cell viability, cellular impedance and flow cytometry-based analyses of cell death. Importantly, the statin also reduced the level of kidney DNA damage and apoptosis triggered by CisPt treatment of mice. The data show that the lipid-lowering drug lovastatin extensively counteracts pro-apoptotic signal mechanisms of the DDR of tubular epithelial cells following CisPt injury.
authors.affiliation: Institute of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Krüger
authors.affiliation: Institute of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Ziegler
authors.affiliation: Institute of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Institute of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Henninger
authors.affiliation: Institute of Cell Biology, University Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Thomale
authors.affiliation: Institute of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupp
authors.affiliation: Institute of Toxicology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany. Electronic address: fritz@uni-duesseldorf.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects* / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats
chemical_list: D008148:Lovastatin; D002945:Cisplatin
keywords: Cisplatin; DNA damage response; Lovastatin; Nephrotoxicity