Growth-Inhibitory and Antiangiogenic Activity of the MEK Inhibitor PD0325901 in Malignant Melanoma with or without BRAF Mutations
Growth-Inhibitory and Antiangiogenic Activity of the MEK Inhibitor PD0325901 in Malignant Melanoma with or without BRAF Mutations
复制标题
DOI：
10.1593/neo.09398
复制
发表时间：
2009-08-01
期刊：
影响因子：
4.8
通讯作者：
Milella, Michele
中科院分区：
文献类型：
--
作者：
Ciuffreda, Ludovica;Del Bufalo, Donatella;Milella, Michele
Raf/MEK/ERK通路是肿瘤细胞增殖和血管生成的重要介质。在这里，我们研究了 PD0325901（一种新型 MEK 抑制剂）在人黑色素瘤细胞中的生长抑制和抗血管生成特性。 PD0325901 的效果是在一组具有不同遗传畸变的黑色素瘤细胞系中确定的。 PD0325901 显着抑制 BRAF 突变型和野生型黑色素瘤细胞系的 ERK 磷酸化和生长，即使在反应最差的模型中，IC50 也在纳摩尔范围内。无论 BRAF 突变状态如何，在异种移植模型中体外和体内均观察到生长抑制，这是由于 G(1) 期细胞周期停滞和随后诱导细胞凋亡所致。 PD0325901 在蛋白质水平上调节细胞周期（细胞周期蛋白 D1、c-Myc 和 p27(KIP1)）和细胞凋亡（Bcl-2 和生存素）调节因子。基因表达谱揭示了参与 MAPK 信号传导负控制和黑色素瘤细胞分化的多个基因的深刻调节，提示了替代的、潜在相关的作用机制。最后，PD0325901 在转录水平抑制促血管生成因子血管内皮生长因子和白细胞介素 8 的产生。总之，PD0325901 在黑色素瘤系中发挥有效的生长抑制、促凋亡和抗血管生成活性，无论其 BRAF 突变状态如何。对 MEK 抑制剂作用的分子机制的更深入了解可能会转化为针对恶性黑色素瘤患者的更有效的治疗策略。
The Raf/MEK/ERK pathway is an important mediator of tumor cell proliferation and angiogenesis. Here, we investigated the growth-inhibitory and antiangiogenic properties of PD0325901, a novel MEK inhibitor, in human melanoma cells. PD0325901 effects were determined in a panel of melanoma cell lines with different genetic aberrations. PD0325901 markedly inhibited ERK phosphorylation and growth of both BRAF mutant and wild-type melanoma cell lines, with IC50 in the nanomolar range even in the least responsive models. Growth inhibition was observed both in vitro and in vivo in xenograft models, regardless of BRAF mutation status, and was due to G(1)-phase cell cycle arrest and subsequent induction of apoptosis. Cell cycle (cyclin D1, c-Myc, and p27(KIP1)) and apoptosis (Bcl-2 and survivin) regulators were modulated by PD0325901 at the protein level. Gene expression profiling revealed profound modulation of several genes involved in the negative control of MAPK signaling and melanoma cell differentiation, suggesting alternative, potentially relevant mechanisms of action. Finally, PD0325901 inhibited the production of the proangiogenic factors vascular endothelial growth factor and interleukin 8 at a transcriptional level. In conclusion, PD0325901 exerts potent growth-inhibitory, proapoptotic, and antiangiogenic activity in melanoma lines, regardless of their BRAF mutation status. Deeper understanding of the molecular mechanisms of action of MEK inhibitors will likely translate into more effective treatment strategies for patients experiencing malignant melanoma.