The isothiocyanate sulforaphane (SF) has received increasing interest of late as a promising chemopreventive agent in several model systems. As a natural product derived from cruciferous vegetables, SF has low toxicity, yet is able to regulate many factors important in tumorigenesis, including inflammation, cell cycle and apoptosis. Our current work is focused on determining whether SF is a good candidate for chemoprevention of UV-induced non-melanoma skin cancer (NMSC). Although there have been two published studies using SF in long-term mouse tumorigenesis experiments, the issue of whether SF can protect against NMSC when used concurrently with UVB treatment has not been addressed. We have therefore treated female SKH-1 hairless immunocompetant mice, 20 per group, with either UVB alone, UVB+Acetone, UVB+1μmol SF or UVB+2.5μmol SF. Mice were treated topically three times a week with either vehicle or SF, one hour prior to treatment with UVB. The UVB dosage started at 0.9 kJ/m2 and increased 25% each week until it reached a maximum intensity of 2.75 kJ/m2 where it was maintained for the remainder of the experiment. The drug/UVB treatment was performed for 25 weeks, with a one week pre-dosing using only drug. The results from this experiment indicate that SF treatment significantly inhibits tumor multiplicity, total and average tumor burden using both of the doses tested when compared to both the UVB alone and the UVB+Acetone controls. Tumor incidence was inhibited only by treatment with 2.5μmol SF. Molecularly, previous work in our laboratory has indicated that UVB activates Cox2 synthesis in keratinocytes through a signaling cascade involving both PI3-Kinase/Akt activation and p38 phosphorylation. We now demonstrate that SF dose-dependently inhibits p38 phosphorylation and Cox2 expression after UVB in human keratinocytes. Akt phosphorylation is not inhibited by SF. Inhibition of Cox2 and p38 by SF is consistent with previous studies that implicate inflammation as a mediator of NMSC promotion. This work was supported by P01 CA27502 and R25 CA78447.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA