In the present study, we investigated the long term antiproliferative potential of iron chelators Salicylaldehyde Isonicotinoyl Hydrazone (SIH), Pyridoxal Isonicotinoyl Hydrazone (PIH) and their caged-derivatives 2-Nitrophenyl Ethyl-SIH and –PIH (2NPE-SIH and 2NPE-PIH) using human primary fibroblast cell line FEK4 and the spontaneously immortalised human keratinocyte cell line, HaCaT as models.We then extended the study to additional hyperproliferative skin keratinocyte cell lines notably MKPS (immortalised psoriatic cell line) as well as PM1 and MET2 that represent two cancerous skin cell lines isolated at different stages of malignant transformation of squameous cell carcinoma (SCC) from a single adult individual. Iron depletion with SIH and its UVA-activated caged-derivative (i.e. 2NPE-SIH) led to significant cell death in all cell models presumably as a result of inhibition of G1/S progression in cell cycle. PIH and 2NPE-PIH on the other hand only caused transient growth retardation in cells due to delayed S Phase but with no apparent toxicity. The growth inhibitory/retardation effects of SIH/PIH or UVA-activated caged-SIH/PIH were related to their iron-chelating properties, as their saturation with iron could reverse their antiproliferative activity in the analysed skin cells. Taken together the results suggested that 2NPE-PIH which possesses very high iron chelating potential, but low antiproliferative activity (i.e. upon uncaging by UVA) is more suitable for skin photoprotection. In contrast, 2NPE-SIH which remains inactive inside the cells until its strong iron binding activity and high antiproliferative properties are activated by UVA, may offer a highly selective and dose-controlled alternative for treatment of hyperproliferative skin disorders such as skin cancer.
|Date of Award||1 Nov 2010|
|Supervisor||Charareh Pourzand (Supervisor) & Olivier Reelfs (Supervisor)|