Lovastatin attenuates ionizing radiation-induced normal tissue damage in vivo.
OBJECTIVE
HMG-CoA-reductase inhibitors (statins) are widely used lipid-lowering drugs. Moreover, they have pleiotropic effects on cellular stress responses, proliferation and apoptosis in vitro. Here, we investigated whether lovastatin attenuates acute and subchronic ionizing radiation-induced normal tissue toxicity in vivo.


METHODS
Four hours to 24h after total body irradiation (6Gy) of Balb/c mice, acute pro-inflammatory and pro-fibrotic responses were analyzed. To comprise subchronic radiation toxicity, mice were irradiated twice with 2.5Gy and analyses were performed 3weeks after the first radiation treatment. Molecular markers of inflammation and fibrosis as well as organ toxicities were measured.


RESULTS
Lovastatin attenuated IR-induced activation of NF-kappaB, mRNA expression of cell adhesion molecules and mRNA expression of pro-inflammatory and pro-fibrotic marker genes (i.e. TNFalpha, IL-6, TGFbeta, CTGF, and type I and type III collagen) in a tissue- and time-dependent manner. gammaH2AX phosphorylation stimulated by IR was not affected by lovastatin, indicating that the statin has no major impact on the induction of DNA damage in vivo. Radiation-induced thrombopenia was significantly alleviated by lovastatin.


CONCLUSIONS
Lovastatin inhibits both acute and subchronic IR-induced pro-inflammatory and pro-fibrotic responses and cell death in normal tissue in vivo. Therefore, lovastatin might be useful for selectively attenuating acute and subchronic normal tissue damage caused by radiotherapy.
Ostrau
Christian
C
Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
Hülsenbeck
Johannes
J
Herzog
Melanie
M
Schad
Arno
A
Torzewski
Michael
M
Lackner
Karl J
KJ
Fritz
Gerhard
G
D000818:Animals; D002470:Cell Survival / Q000528:radiation effects; D004249:DNA Damage; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000032:analysis; D007422:Intestines / Q000528:radiation effects; D008099:Liver / Q000528:radiation effects; D008148:Lovastatin / Q000494:pharmacology*; D008168:Lung / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism*; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000517:prevention & control*; D011833:Radiation Injuries, Experimental; D011839:Radiation, Ionizing; D011897:Random Allocation; D012016:Reference Values; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000528:radiation effects
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D008148:Lovastatin