title: The phototumorigenic fluoroquinolone, lomefloxacin, photosensitises p53 accumulation and transcriptional activity in human skin cells.
abstract: The fluoroquinolone antibiotic, lomefloxacin, is phototoxic in human skin exposed to UVA radiation, photosensitises DNA strand breaks and pyrimidine dimers in human keratinocytes in vitro, and is phototumorigenic in mouse skin. The p53 tumour suppressor protein is activated by a variety of cellular insults including UV radiation, to become a transcription factor for downstream markers such as the cyclin-kinase inhibitor p21CIP1/WAF1 or cause caspase transactivation which cleaves poly ADP ribose polymerase (PARP) as an early step in apoptosis. We have investigated these molecular defence responses in human skin cells treated with lomefloxacin and UVA radiation in vitro. Western blots revealed that lomefloxacin photosensitised the stabilisation of p53 protein in human fibroblasts. Lomefloxacin also photosensitised p53 transcriptional activity in amelanotic melanoma cells expressing wild-type p53 and stably transfected with a construct containing a beta-galactosidase reporter gene downstream from a p53 consensus binding sequence. Neither photosensitised production of H2O2 nor the resultant DNA strand breaks, appeared to be involved in this effect. Interestingly, p21CIP1/WAFI protein was upregulated by lomefloxacin in the dark by a p53-independent mechanism. Lomefloxacin also photosensitised the degradation of nuclear PARP, suggestive of caspase mediated, early apoptotic events.
authors.affiliation: Photobiology Unit, University of Dundee, Ninewells Hospital, UK.
authors.forename: S
authors.initials: S
authors.lastname: Kidd
authors.forename: J R
authors.initials: JR
authors.lastname: Meunier
authors.forename: N J
authors.initials: NJ
authors.lastname: Traynor
authors.forename: L
authors.initials: L
authors.lastname: Marrot
authors.forename: C
authors.initials: C
authors.lastname: Agapakis-Causse
authors.forename: N K
authors.initials: NK
authors.lastname: Gibbs
mesh_terms: D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D024841:Fluoroquinolones; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015394:Molecular Structure; D017319:Photosensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D012867:Skin / Q000166:cytology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000890:Anti-Infective Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D024841:Fluoroquinolones; D017319:Photosensitizing Agents; D015363:Quinolones; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; C053091:lomefloxacin