Molecular response to phototoxic stress of UVB-irradiated ketoprofen through arresting cell cycle in G2/M phase and inducing apoptosis.
The phototoxicity of ketoprofen (KP), a non-steroidal anti-inflammatory drug, has recently attracted considerable attention, because it is photolabile and undergoes degradation when irradiated by sunlight to induce various skin diseases. The present study shows that combination of UVB irradiation with KP induced the cytotoxicity and suppressed DNA synthesis in HaCaT cells in a concentration-dependent manner. UVB-irradiated KP inhibited the cell growth and induced G2/M cell cycle arrest by modulating the levels of cdc2, cyclin B1, Chk1, Tyr15-phosphorylated cdc2 and p21. It also provoked a striking accumulation of cyclin B1-cdc2-p21 complexes, concomitantly with an increase in the levels of Tyr15-phosphorylated cdc2 and p21 protein. The presence of KP accentuated the apoptotic response to UVB radiation in HaCaT cells as evidenced by DAPI staining. The apoptotic process was associated with activation of caspase-9, caspase-3 and cleavage of PARP, and this activation could be prevented by a specific caspase-3 inhibitor. Taken together, our results suggest that KP-photoinduced apoptosis may be a useful approach to reduce or prevent skin carcinogenesis.
Liu
Shicheng
S
Research Department, Saitama Daiichi Pharmaceutical Co., Ltd., 8-1, Minamisakae-cho, Kasukabe, Saitama 344-0057, Japan. riu@sdsk.co.jp
Mizu
Hideo
H
Yamauchi
Hitoshi
H
D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D016195:G2 Phase / Q000187:drug effects / Q000528:radiation effects; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D007660:Ketoprofen / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects*; D014466:Ultraviolet Rays
D007660:Ketoprofen