Combinatorial Approach for Prevention of Melanoma

在美国，黑色素瘤的发病率几乎比任何其他恶性肿瘤增加了15倍。转移性黑色素瘤患者的预后仍然很差，尽管治疗的进步，强调预防措施的重要性。RAF-MEK-ERK（MAPK）通路是黑色素瘤细胞增殖的关键调节因子，其中ERK在高达90%的人类黑色素瘤中被过度激活。索拉非尼是一种口服活性多激酶药物，是一种有效的RAF抑制剂。使用索拉非尼作为单一疗法缺乏临床功效已经导致探索其它预防/治疗方案，其中索拉非尼可以与其它途径抑制剂组合以用于更有效的协同作用的肿瘤抑制。在黑色素瘤发病机制方面有许多进展，包括鉴定了组成性激活并在黑色素瘤进展中起主要作用的P13 KAKT- mTOR（AKT）信号通路。在这方面，MAPK和AKT信号转导通路可能是有效预防黑色素瘤的有希望的靶点。这些进展正在被利用来提供靶向药物和新的治疗方法。靶向MTOR途径似乎是一种有前途的策略。不幸的是，雷帕霉素（mTOR抑制剂）及其类似物（雷帕霉素类似物）在黑色素瘤治疗中并不成功。因此，寻找新的和更有效的mTOR抑制剂是最重要的兴趣。非瑟酮（3，7，3 prime，4 prime-tetrahydroxyflavone）是一种天然存在的类黄酮，存在于许多水果和蔬菜中。它在癌细胞中具有抗增殖、凋亡和抗氧化活性。最近，我们发现非瑟酮在两个位点与mTOR复合物相互作用。非瑟酮处理降低了黑色素瘤细胞中mTOR在Ser 2448和Ser 2481处的磷酸化，并降低了raptor（形成mTOR复合物1，mTORCl）和rictor（形成mTOR复合物2，mT 0 RC 2）的蛋白表达。此外，用fesetin（10-60 μ M; 48小时）处理黑素瘤细胞系（如451 Lu、A375和Mel 928）降低了细胞活力，但对正常人黑素细胞的影响最小。

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.