1. ¹Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, UK
2. ²Centre for Biomolecular Sciences, School of Chemistry, University of Nottingham, University Park, Nottingham, UK
3. ³These authors contributed equally to this work

Correspondence: Dr Charareh Pourzand, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK. E-mails: prscap@bath.ac.uk; James Dowden, james.dowden@nottingham.ac.uk

Received 4 January 2006; Revised 15 March 2006; Accepted 16 March 2006; Published online 18 May 2006.

Abstract

Exposure of human skin cells to solar UVA radiation leads to an immediate dose-dependent increase of labile iron that subsequently promotes oxidative damage and necrotic cell death. Strong iron chelators have been shown to suppress cell damage and necrotic cell death by moderating the amount of labile iron pool (LIP), but chronic use would cause severe side effects owing to systemic iron depletion. Prodrugs that become activated in skin cells at physiologically relevant doses of UVA, such as "caged-iron chelators", may provide dose- and context-dependent release. Herein, we describe prototypical iron chelator compounds derived from salicylaldehyde isonicotinoyl hydrazone and pyridoxal isonicotinoyl hydrazone and demonstrate that the intracellular LIP and subsequent necrotic cell death of human skin fibroblasts is significantly decreased upon exposure to a combination of the prototypical compounds and physiologically relevant UVA doses. Iron regulatory protein bandshift and calcein fluorescence assays reveal decreased intracellular LIP following irradiation of caged-chelator-treated cells, but not in control samples where either UVA light, or caged-chelator is absent. Furthermore, flow cytometry shows that these compounds have no significant toxicity in the skin fibroblasts. This novel light-activated prodrug strategy may therefore be used to protect skin cells against the deleterious effects of sunlight.