Lovastatin causes sensitization of HeLa cells to ionizing radiation-induced apoptosis by the abrogation of G2 blockage.
OBJECTIVE
To investigate the effect of inhibition of Ras/Rho-regulated signalling by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on radiation-induced cell killing and apoptosis.


METHODS
Different human cell lines were pretreated or not with lovastatin before exposure to gamma-rays. Afterwards, radiation-induced cell killing, formation and repair of double-strand breaks, activation of radiation-inducible signal mechanisms (i.e. p53, p21, extracellular-signal-related kinase (ERK), NF-kappaB), changes in cell cycle progression and apoptosis were analysed.


RESULTS
As shown by a colony formation assay, lovastatin sensitized HeLa cells to gamma-radiation-induced cell killing. The lovastatin effect was cell-type specific. Neither the level of gamma-ray-induced double-strand breaks nor its repair were affected by lovastatin. Sensitization was independent of p53/p21Waf1- and NF-kappaB-related mechanisms. Radiation-stimulated activation of ERKs was attenuated by lovastatin. Cell cycle analyses revealed that the level of gamma-ray-induced G2 blockage was not affected by lovastatin. However, as analysed up to 72 h after irradiation, lovastatin pretreated cells showed an accelerated abrogation of G2 blockage as compared with the control. G2 abrogation is paralleled by an increase in the frequency of apoptotic and necrotic cells.


CONCLUSIONS
The data show that lovastatin can render human cells more sensitive to the cytotoxic effect of gamma-rays. This is related to abrogation of G2 blockage and a concomitant increase in apoptotic/necrotic cell death.
Fritz
G
G
Institute of Toxicology, Division of Applied Toxicology, University of Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany. fritz@mail.uni-mainz.de
Brachetti
C
C
Kaina
B
B
D017209:Apoptosis / Q000528:radiation effects*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000032:analysis; D004249:DNA Damage; D016195:G2 Phase / Q000187:drug effects*; D005720:Gamma Rays; D006367:HeLa Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D008148:Lovastatin; D020928:Mitogen-Activated Protein Kinases