Melanoma is the most invasive and deadly form of skin cancer with few chemopreventive agents available to treat this deadly disease. Currently, the major preventive strategy for melanoma involves early detection and surgical removal. Despite these preventive strategies and use of sunscreen, incidence and mortality rates of melanoma continues to rise ~ 4% per year in the US and worldwide. Knowledge of this problem is driving the search for new compounds targeting pathways is important in melanoma development. Deregulated Akt3 signaling is critical to development of ~70% of melanoma making targeting of this pathway key for any effective therapeutic regime. To identify new agents targeting Akt3 signaling in melanoma, a natural product library was screened for a candidate compound inducing apoptosis by targeting this pathway. Plumbagin was identified from this screen. The hypothesis to be tested is that plumbagin targets a member of the Akt3 signaling cascade to inhibit pathway activity thereby inducing apoptosis and retarding tumor development. The objective of this application is to characterize the chemopreventive utility of plumbagin in melanoma cells, which inhibits Akt3 signaling and establish the mechanistic basis by which the compound prevents melanoma development. Preliminary data presented below support this hypothesis by: (1) showing identification of plumbagin from a natural compound library screen as a potent inhibitor of melanoma cells;(2) that plumbagin inhibits Akt3 signaling in melanoma cells and induces apoptosis;(3) demonstrating that plumbagin reduces cell viability by decreasing cellular proliferation and inducing apoptosis;and (4) validating the chemopreventive potential of plumbagin by showing that the compound inhibits melanoma development in lab generated skin. This discovery would be highly significant, providing novel insight into the chemopreventive implications of targeting a major signaling pathway promoting development of ~70% of melanoma.
For melanoma patients and the general public, discovery of plumbagin as an effective melanoma chemopreventive agent would have potential to significantly impact human health by decreasing number of persons inflicted with melanoma, thereby directly decreasing mortality rates. Therefore, the positive impact for reducing melanoma incidence and mortality rates would be significant.
