The phototumorigenic fluoroquinolone, lomefloxacin, photosensitises p53 accumulation and transcriptional activity in human skin cells

Samantha Kidd, Jean Roch Meunier, Nicola J. Traynor, Laurent Marrot, Catherine Agapakis-Causse, Neil K. Gibbs

    Research output: Contribution to journalArticlepeer-review

    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 p21(CIP1/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 β-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, p21(CIP1/WAF1) 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. (C) 2000 Elsevier Science B.V. All rights reserved.
    Original languageEnglish
    Pages (from-to)26-31
    Number of pages5
    JournalJournal of Photochemistry and Photobiology, B: Biology
    Volume58
    Issue number1
    DOIs
    Publication statusPublished - 2000

    Keywords

    • Fluoroquinolones
    • Lomefloxacin
    • P2(CIPI/WAFI)
    • P53
    • PARP
    • Photocarcinogenesis

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