1,25-Dihydroxyvitamin D3 and analogues protect primary human keratinocytes against UVB-induced DNA damage.
Exposure to UVB irradiation is a major risk factor for the development of skin cancer. Therefore, it is important to identify agents that can offer protection against UVB-caused damage. Photocarcinogenesis is caused largely by mutations at sites of incorrectly repaired DNA photoproducts, of which the most common are the cyclobutane pyrimidine dimers (CPDs). In this study, we demonstrated that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] protects primary human keratinocytes against the induction of CPDs by UVB. This protection required pharmacologic doses 1,25(OH)2D3 and an incubation period of at least 8 h before irradiation. Furthermore, we provided arguments indicating that the anti-proliferative capacity of 1,25(OH)2D3 underlies its protective effect against UVB-induced DNA damage. Finally, we showed that 19-nor-14-epi-23-yne-1,25(OH)2D3 (TX 522) and 19-nor-14,20-bisepi-23-yne-1,25(OH)2D3 (TX 527), two low-calcemic analogues of 1,25(OH)2D3, were even 100 times more potent than the parent molecule in inhibiting UVB-caused DNA damage. These molecules are therefore promising candidates for the chemoprevention of UVB-induced skin cancer.
De Haes
Petra
P
Laboratory for Experimental Medicine and Endocrinology, Onderwijs en Navorsing, Katholieke Universiteit Leuven, Gasthuisberg, Herestraat 49, Bus 902, 3000 Leuven, Belgium.
Garmyn
Marjan
M
Verstuyf
Annemieke
A
De Clercq
Pierre
P
Vandewalle
Maurits
M
Degreef
Hugo
H
Vantieghem
Katleen
K
Bouillon
Roger
R
Segaert
Siegfried
S
D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000528:radiation effects*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D011740:Pyrimidine Dimers / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*
D011740:Pyrimidine Dimers; D016159:Tumor Suppressor Protein p53; C118756:dihydroxy-vitamin D3; D014807:Vitamin D