Lovastatin enhances the photocytotoxicity of UVA radiation towards cultured N.C.T.C. 2544 human keratinocytes: prevention by cholesterol supplementation and by a cathepsin inhibitor.
The effect of the hydroxymethylglutaryl-CoA (HMG-CoA) inhibitor lovastatin on the UVA-induced photocytotoxicity has been investigated in cultured human N.C.T.C. 2544 keratinocytes. In the absence of irradiation, 5 x 10(-7) M lovastatin did not exhibit any significant cytotoxic effect towards this cell line. Although the drug cannot act as a photosensitizer, because it does not absorb in the UVA range, it markedly increased the UVA-induced cellular damage (about 70% reduction in cell viability at 5 x 10(-7) M). This effect was not accompanied by an increase in the lipid peroxidation product content of cells as compared with treatment with UVA alone. Medium supplementation with 0.01 mg/ml free cholesterol totally prevented the enhancement of UVA photocytotoxicity induced by lovastatin. A protective effect was also observed when cells were supplemented with an amount of low-density lipoprotein giving the same cholesterol concentration in the culture medium. Finally, E64 [L-trans-epoxysuccinyl-leucylamido-(4-guanidino)-butane], a lysosomal cathepsin inhibitor, also prevents the cell death induced by UVA in cells treated with lovastatin. These results suggest that HMG-CoA reductase inhibitors could increase the sensitivity of skin cells to UVA radiation, and that this phenomenon is related to lysosomal enzyme release.
Quiec
D
D
Laboratoire de Biochimie, Faculté de Médecine St. Antoine, Paris, France.
Mazière
C
C
Auclair
M
M
Santus
R
R
Gardette
J
J
Redziniak
G
G
Franchi
J
J
Dubertret
L
L
Mazière
J C
JC
D002403:Cathepsins / Q000037:antagonists & inhibitors; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002784:Cholesterol / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000528:radiation effects; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008148:Lovastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014466:Ultraviolet Rays
D002784:Cholesterol; D008148:Lovastatin; D002403:Cathepsins; D007930:Leucine; C024974:E 64