Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model
Inhibition of phosphatidylinositol-3-kinase and mitogen-activated protein kinase kinase 1/2 prevents melanoma development and promotes melanoma regression in the transgenic TPRas mouse model
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DOI：
10.1158/1535-7163.mct-06-0269
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发表时间：
2006-12-01
影响因子：
5.7
通讯作者：
Broome Powell, Marianne
中科院分区：
文献类型：
--
作者：
Bedogni, Barbara;Welford, Scott M.;Broome Powell, Marianne
许多人类黑色素瘤由于该分子的突变或上游或下游效应分子的改变而呈现Ras通路的过度激活。在这项研究中，我们评估了在TPRas小鼠模型中阻断Ras的两个下游通路——磷脂酰肌醇 - 3 - 激酶/Akt和Raf/丝裂原活化蛋白激酶激酶/细胞外信号调节激酶对黑色素瘤发生和消退的影响。局部应用Ly294002和U0126对这两个信号级联的抑制显著延缓了黑色素瘤的发生，并显著降低了肿瘤的发生率，尤其是当两种药物联合应用时。当联合给药时，对已形成的黑色素瘤使用抑制剂进行治疗，33%的小鼠完全缓解，46%的小鼠部分消退。这些反应与体内外细胞凋亡增加、增殖减少以及肿瘤血管生成减少相关。总之，这项研究有力地支持了磷脂酰肌醇 - 3 - 激酶/Akt和Raf/丝裂原活化蛋白激酶激酶/细胞外信号调节激酶通路在Ras依赖性黑色素瘤的发生和维持中的作用，并支持这样一种观点，即对这些效应分子的特异性抑制可能是治疗和预防该疾病的一种非常有前景的途径。
A number of human melanomas show hyperactivation of the Ras pathway due to mutations of the molecule or alteration of upstream or downstream effectors. In this study, we evaluated the effect of blocking the two Ras downstream pathways phosphatidylinositol-3-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase on melanoma development and regression in the TPRas mouse model. The inhibition of these two signaling cascades by topically applied Ly294002 and U0126 significantly delayed melanoma development and significantly decreased the tumor incidence, particularly when the drugs were applied in combination. Treatment with the inhibitors of established melanomas resulted in complete remission in 33% of mice and partial regression in 46% of mice when drugs were delivered in combination. These responses correlated with increased apoptosis and decreased proliferation both in vitro and in vivo and reduced tumor angiogenesis. In conclusion, this study strongly supports the role of the phosphatidylinositol-3-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways in the development and maintenance of Ras-dependent melanomas and supports the notion that specific inhibition of these effectors may represent a very promising avenue for the treatment and prevention of the disease.