Title: Towards the use of mechanism-based chemopreventive agents to reduce the incidence of skin cancer
Funder: Cancer Research UK

Abstract: Increased susceptibility to skin cancer is a major cause of morbidity amongst solid organ transplant recipients, who suffer an incidence of squamous cell carcinoma that is &#126;200-fold greater than the general population. Exposure to ultraviolet radiation (UVR), aerobic life, genetic susceptibility, viral infections, and immunosuppressive therapy are all contributing factors. UVR damages DNA directly, but also leads to generation of reactive oxygen intermediates (ROI) resulting in inflammation, and immunosuppression. Furthermore, the deleterious effects of sunlight exposure in transplant patients are compounded by interactions between UVA radiation and thiopurine immunosuppressive drugs, again resulting in ROI-mediated damage. The detrimental consequences of ROI are counteracted by a family of genes encoding cytoprotective proteins (e.g., glutathione transferases, NAD(P)H:quinone oxidoreductase 1, heme oxygenase 1) the expression of which is up-regulated by small molecules (chemopreventive inducers) via the Keap1/Nrf2/ARE pathway. The proposed study will test the hypothesis that induction of intrinsic cytoprotective proteins via the Keap1/Nrf2/ARE pathway provides protection against UVR-induced skin damage and photocarcinogenesis under both normal conditions and during thiopurine-based immunosuppressive therapy. AIM1 will characterize the response to UVR (e.g., generation of ROI, damage to DNA, proteins, and lipids, induction of apoptosis) in keratinocytes and dermal fibroblasts under basal conditions and following treatment with sulforaphane, a potent inducer of the Keap1/Nrf2/ARE pathway. We will also determine whether sulforaphane can protect against the synergistic damaging action of UVA radiation and 6-thioguanine, a surrogate for the commonly used immunosuppressive drug azathioprine. AIM2 will establish whether either down-regulation or constitutive activation of Keap1/Nrf2-dependent cytoprotective proteins influences the susceptibility to damage by UVR in vivo using mice lacking either Nrf2 (the major transcription factor responsible for basal and inducible expression of cytoprotective genes) or Keap1 (the protein sensor for inducers and a repressor of Nrf2) specifically in the skin. The ability of sulforaphane to protect against skin carcinogenesis under immunosuppressive conditions will be tested using a mouse model of chronic exposure to low doses (comparable to human exposures) of UVR by comparing the latency, incidence, multiplicity, and volume of skin tumours that develop in animals receiving immunosuppressive azathioprine treatment with immunocompetent controls. AIM3 will determine the effect of induction of cytoprotective proteins on the photosensitivity to UVR in the skin of healthy human subjects. The findings will pave the road for subsequent clinical develpopment of topical chemopreventive inducers of cytoprotective proteins as much needed mechanism-based agents for the effective reduction of the incidence of skin cancer. Last updated 21/07/2010


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS