Combinatorial Approach for Prevention of Melanoma

预防黑色素瘤的组合方法

• 批准号: 8538752
• 负责人: FARRUKH AFAQ
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538752
• 关键词: AKT Signaling Pathway; Adherent Culture; Advocacy; Animal Model; Apoptosis; Apoptotic; Apple; BAY 54-9085; BRAF gene; Cell Line; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chemopreventive Agent; Clinical Research; Complex; Cucumber; Data; Diet; Diospyros; Drug Targeting; Epidemiology; Failure; Flavonoids; Growth; Human; Immunotherapy; Implant; In Vitro; Incidence; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MEKs; Malignant Neoplasms; Measures; Melanoma Cell; Metastatic Melanoma; Neoplasm Metastasis; Nude Mice; Oncogenes; Oncogenic; Onions; Pathogenesis; Pathway interactions; Patients; Phase; Phosphorylation; Plants; Prevention; Prevention approach; Prevention strategy; Preventive; Proto-Oncogene Proteins c-akt; Raptors; Regimen; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sirolimus; Site; Strawberries; Survival Rate; Testing; Therapeutic; Toxic effect; United States; analog; base; cancer cell; chemotherapy; clinical efficacy; combinatorial; fisetin; fruits and vegetables; human FRAP1 protein; in vivo; inhibitor/antagonist; interest; mTOR Inhibitor; melanocyte; melanoma; novel; novel therapeutic intervention; outcome forecast; protein expression; skin disorder; tumor; tumor growth

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.

在美国，黑色素瘤的发病率几乎是其他任何恶性肿瘤的15倍以上。尽管治疗取得了进步，转移性黑色素瘤患者的预后仍然很差，强调了预防措施的重要性。RAF-MEK-ERK(MAPK)通路是黑色素瘤细胞增殖的关键调节因子，在高达90%的人类黑色素瘤中ERK处于过度激活状态。索拉非尼是一种口服活性多激酶剂，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疗效，这导致了对其他预防/治疗方案的探索，在这些方案中，索拉非尼可以与其他途径抑制剂联合使用，以实现更有效、协同作用的肿瘤抑制。黑色素瘤的发病机制有许多进展，包括发现了P13KAKT-mTOR(AKT)信号通路，该信号通路是结构性激活的，在黑色素瘤的发展中起着重要作用。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效靶点。这些进展正在被利用来提供靶向药物和新的治疗方法。以MTOR途径为靶点似乎是一个很有前途的策略。不幸的是，雷帕霉素(mTOR抑制剂)及其类似物(雷帕洛格)在治疗黑色素瘤方面并不成功。因此，寻找新的、更有效的mTOR抑制剂是非常有意义的。鱼腥草素(3，7，3，4-四羟基黄酮)是一种天然存在的类黄素，存在于许多水果和蔬菜中。它在癌细胞中具有抗增殖、抗凋亡和抗氧化活性。最近，我们发现Fisetin在两个位点与mTOR复合体相互作用。非瑟素处理后，黑色素瘤细胞中mTOR在Ser2448和Ser2481处的磷酸化程度降低，Raptor(形成mTOR复合体1，mTORCI)和Rictor(形成mTOR复合体2，mT0RC2)的蛋白表达降低。此外，用Fesetin(10-60微米；48小时)处理黑色素瘤细胞系(如451Lu、A375和Mel928)会降低细胞存活率，但对正常人黑素细胞的影响很小。