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Skin cancer is one of the most prevalent diseases of the modern world. Each year, approximately 1.2 million new cases of skin cancer are diagnosed in the United States, which account for roughly 40% of all new cancer cases. The majority of these skin cancer cases are classified as non-melanoma skin cancer (NMSC). NMSC occur primarily on sun-exposed areas of the body and have been attributed to cumulative cellular changes brought about by ultraviolet (UV) light radiation. Recent rising rates of NMSC have been attributed to many factors, including increased outdoor activity, an increase in lifespan, and an increase in the UV index due to reductions in the ozone layer. In addition, there is an alarming amount of aggressive NMSCs found in organ transplant patients who are taking immune-suppressive drugs. Although there is heightened awareness about the need for limited sun exposure and use of sunscreens, this has not significantly impacted NMSC incidence. Therefore, we must search for better methods to prevent NMSC, in formats which are affordable and manageable for public use. We are investigating the use of the natural product sulforaphane as a possible preventive treatment for UV-induced NMSC.
Sulforaphane (SFN) is a type of isothiocyanate derived from Cruciferous vegetables, especially broccoli and broccoli sprouts. SFN and other isothiocyanates have gained attention in recent years as being powerful inhibitors of tumorigenesis in various laboratory cancer models, including lung cancer, colon cancer and skin cancer. Although SFN has many interesting activities in the cell, we are currently focusing on two of its targets that may be relevant to skin cancer: 1) The ability of SFN to activate cellular defenses through stimulation of the Nrf2 transcription factor, and 2) The ability of SFN to inhibit the growth potential of tumorigenic cells through blocking the activity of the AP-1 transcription factor. Although the effect of SFN treatment on Nrf2 is well-defined in many cell types, it is not known whether Nrf2 stimulation is protective in UV-induced skin carcinogenesis. Inhibition of AP-1, on the other hand, is known to significantly reduce UV-induced NMSC rates, using both pharmacological and genetic means. We have recently shown that SFN blocks the activity of AP-1 after UV stimulation in keratinocytes, and it does so by specifically binding to a redox-sensitive cysteine in the DNA binding domain of the AP-1 protein. We are currently generating mouse models to test the importance of both Nrf2 and AP-1 in the response to SFN during UV-induced skin carcinogenesis experiments. In addition, we are in the process of formulating SFN into a cream for clinical testing in Phase 0 and Phase 1 trials in the near future. We hope to someday show that SFN can be beneficial in preventing NMSC in human skin, or even reversing some latent damage caused by sun exposure.
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