Studies on the Therapeutic Potential of Natural and Synthetic Iron Chelators

Abstract

Human skin is continuously exposed to solar ultraviolet A (UVA, 320-400 nm). Absorption of UVA rays by intracellular chromophores, such as porphyrins, triggers the generation of reactive oxygen species (ROS) in skin cells which induces direct oxidative damage to cell constituents. Research from our laboratory shows that UVA also induces an immediate increase in the cytosolic pool of labile iron (LI) that intensifies the oxidative damage already occurring in the skin cells, and may also exacerbate skin damage caused by further UVA exposure. Because of the damaging role of LI in UVA-induced oxidative damage, iron chelators are thought to be valuable tools in reducing iron-catalysed damage in skin cells. This has provided a strategy to use iron chelators as photoprotectants with the intent of incorporating the chelating molecules as ingredients to sunscreen formulations designed to protect against both UVA and UVB components of sunlight.

Previous work in this laboratory has shown that limited exposure of skin cells to the strong hexadentate clinical iron chelator desferrioxamine (DFO) provides adequate protection against oxidative damage and cell death caused by UVA radiation, but the hydrophilic nature and size of DFO exclude its use for skin photoprotection via topical application. In contrast bidentate and tridentate clinical chelators such as Deferiprone (DFP) and Deferasirox (DFX) with more suitable lipophilicity and lower molecular weight may be better candidates for photoprotection against UVA-induced LI-mediated damage. The drawback of such chelators is that they do not possess strong iron chelating ability when cell iron concentrations are low. Alternatively natural compounds endowed with either iron scavenging activity alone (e.g. maltol) or with combined antioxidant activity (e.g. kojic acid) may be better photoprotectants against UVA-induced adverse effects.

In the present study, we first evaluated the inherent cytotoxicity/antiproliferative activity of a series of bidentate (DFP, CP94, kojic acid and maltol) and tridentate (DFX, salicylaldehyde isonicotinoyl hydrazone, SIH) iron chelators in human primary skin fibroblasts, FEK4, up to 48 h after the treatments, using the spectrophotometric MTT assay. None of the compounds showed significant cytotoxicity up to the tested concentration of 100 μM. We then chose an example of a bidentate (DFP) and a tridentate (DFX) chelator to investigate their level of protection against UVA-mediated oxidative damage and cell death 24 and 48 h after UVA irradiation using both the MTT assay and the flow cytometric annexin V/propidium iodide uptake assay. Our results show that both chelators are able to provide significant protection against UVA-induced oxidative damage and necrotic cell death at the highest concentration tested of 100 μM. These results strongly suggest that both DFP and DFX may be used as effective UVA photoprotectants in sunscreen formulations.

Date of Award	16 Jun 2021
Original language	English
Awarding Institution	University of Bath
Supervisor	Albert Bolhuis (Supervisor) & Ian Eggleston (Supervisor)