Preventive approaches advocated for skin cancer such as the use of sunscreens and wearing protective clothing have not yielded the desired decline in skin cancers diagnosed. For this reason, additional approaches are needed to more effectively prevent photocarcinogenesis through a process we call photochemoprevention such as with the use of dietary antioxidant substances. Consistent with this notion there has been considerable interest in the identification of natural non-toxic dietary agents that are capable of affording protection to skin from the adverse effects of solar ultraviolet B (UVB) radiation. Pomegranate (Punica granatum L) fruit possesses strong anti-oxidant, anti-inflammatory and anti-proliferative properties. We earlier reported that oral feeding of pomegranate fruit extract (PFE) inhibited both single and multiple UVB radiation-induced short-term biomarkers of photocarcinogenesis in SKH-1 hairless mouse skin. Here, we determined whether oral feeding of PFE can inhibit UVB-mediated skin tumorigenesis. We used a UVB initiation-promotion protocol in which the control mice were subjected to UVB exposure of 180 mJ/cm2, twice a week for thirty weeks. The experimental animals received the same exposure protocol but also received PFE (0.2% w/v) ad libitum in drinking water starting 14 days before UVB exposure and continuing till the termination of the experiment. Compared to non PFE-treated animals, oral feeding of PFE resulted in reduced skin cancer development when expressed in terms of percent of mice with tumors and tumor multiplicity. Tumor appearance in UVB alone group occurred at the 12th week, which was delayed by 3 weeks in mice that received PFE. This inhibitory trend persisted throughout the course of the experiment. Additional studies were performed to examine the associated mechanisms of these inhibitory effects. STAT3 and NF-κB are constitutively active in many human tumors and contribute to photocarcinogenesis. Oral feeding of PFE showed a significant decrease in the phosphorylation of STAT3 (Tyr705) and NF-κB/p65 (Ser536) in uninvolved-skin from tumor-bearing mice and skin tumors compared to non PFE-treated animals. We also found a concomitant decrease in the protein expressions of iNOS, and COX-2, which are potential downstream targets of STAT3 and NF-κB. Moreover, there was a decrease in the protein levels of HIF-1α in tumors of mice that received PFE. Since HIF-1α is associated with neovascularization, we next examined the expression of VEGF and CD31, and observed a significant decrease in their protein levels. These data suggest that PFE has the potential to protect against skin tumorigenesis in mouse model of photocarcinogenesis, at least in part, by modulating transcription factors STAT3, NF-κB and HIF-1α leading to decrease in inflammatory and angiogenic responses, and provide a molecular basis for its photochemopreventive effect.
99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA