Combinatorial Approach for Prevention of Melanoma

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The incidence of melanoma has increased almost 15-folds more than any other malignancy in the United States. The prognosis of patients with metastatic melanoma remains poor in spite of treatment advances, emphasizing the importance of preventive measures. The RAF-MEK-ERK (MAPK) pathway is the key regulator of melanoma cell proliferation, with ERK being hyperactivated in up to 90% of human melanomas. Sorafenib, an orally active multikinase agent, is a potent inhibitor of RAF. Lack of clinical efficacy using sorafenib as a monotherapy has led to the exploration of other preventive/therapeutic regimens in which sorafenib can be combined with other pathway inhibitors for more effective, synergistically acting tumor inhibition. There are many advances in melanoma pathogenesis, including the identification of the P13KAKT- mTOR (AKT) signaling pathway that is constitutively activated and has a major role in the progression of melanoma. In this regard, the MAPK and AKT signal transduction pathways may be promising targets for effective prevention of melanoma. These advances are being exploited to provide targeted drugs and new therapeutic approaches. Targeting the MTOR pathway appears to be a promising strategy. Unfortunately, rapamycin (mTOR inhibitor) and its analogs (rapalogs) have been unsuccessful in melanoma treatment. Therefore, finding novel and more effective inhibitors of mTOR is of paramount interest. Fisetin (3,7,3 prime, 4 prime-tetrahydroxyflavone), a naturally occurring flavinoid, is found in many fruits and vegetables. It possesses antiproliferative, apoptotic and antioxidative activities in cancer cells. Recently, we found that fisetin interacts with the mTOR complex at two sites. Fisetin treatment reduced the phosphorylation of mTOR at Ser2448 and Ser 2481 and decreased the protein expression of raptor (forming mTOR complex 1, mTORCI) and rictor (forming mTOR complex 2, mT0RC2) in melanoma cells. In addition, treatment of melanoma cell lines (such as 451 Lu, A375 and Mel928) with fesetin (10-60 uM; 48 hrs) decreased cell viability but had minimal effect on normal human melanocytes.