The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines
The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant schwannoma cell lines
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DOI：
10.1124/jpet.105.091454
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发表时间：
2006-01-01
影响因子：
3.5
通讯作者：
Reiners, JJ
中科院分区：
文献类型：
--
作者：
Mattingly, RR;Kraniak, JM;Reiners, JJ
1型神经纤维瘤病（NF1）是一种常见的常染色体显性遗传病，导致神经外胚层肿瘤。NF1肿瘤抑制基因编码神经纤维蛋白，其中包括一个用于Ras失活的gtpase激活域。亲和纯化表明，在来自NF1患者的两个独立神经纤维肉瘤细胞系（ST88-14和NF90-8）中，N-Ras是Ras的主要激活亚型。与维持神经纤维蛋白表达（STS-26T）的散发性恶性神经鞘瘤细胞系相比，这些NF1细胞也显示出细胞外信号调节激酶1和2 （ERK1,2）丝裂原活化蛋白（MAP）激酶的组成活性增加。因此，MAP激酶激酶（MEK）抑制剂可能是NF1治疗的合理方法。MEK抑制剂PD98059[2′-氨基-3′-甲氧基黄酮]、PD184352（也称为CI-1040）[2-（2-氯-4-碘-苯胺）- n-环丙基甲氧基3,4-二氟苯酰胺]和U0126[1,4-二氨基-2,3-二氰-1,4-二（2-氨基苯基硫）丁二烯]均对三种细胞系的增殖产生浓度依赖性抑制。单个MEK抑制剂在所有三种细胞系中都有相似的效果。然而，只有PD184352的抗增殖作用与ERK1,2 MAP激酶活性的消除密切相关。PD98059主要具有细胞抑制作用，而U0126和PD184352主要具有细胞毒性。从形态学、DEVDase的激活、procaspase-3的切割以及DNA含量低于G(0)/G(1)的群体的出现可以看出，只有PD184352诱导了所有三种细胞系的凋亡。MEK抑制剂对细胞存活的不同影响并不依赖于p53状态或对ERK5通路的影响。PD184352对原代大鼠雪旺细胞也有促凋亡作用。因此，尽管PD184352能有效杀死神经纤维肉瘤细胞，但其对正常雪旺细胞的影响可能会限制其临床应用。
Type 1 neurofibromatosis ( NF1) is a common autosomal dominant disorder that results in neuroectodermal tumors. The NF1 tumor-suppressor gene encodes neurofibromin, which includes a GTPase-activating domain for Ras inactivation. Affinity purification showed N-Ras to be the predominant activated isoform of Ras in two independent neurofibrosarcoma cell lines from NF1 patients ( lines ST88-14 and NF90-8). These NF1 cells also demonstrated increased constitutive activity of the extracellular signal-regulated kinases 1 and 2 ( ERK1,2) mitogen-activated protein ( MAP) kinases compared with a sporadic malignant schwannoma cell line that maintains neurofibromin expression ( STS-26T). Thus, MAP kinase kinase ( MEK) inhibitors may be a rational approach to NF1 therapy. The MEK inhibitors PD98059 [ 2'-amino-3'-methoxyflavone], PD184352 ( also called CI-1040) [ 2-( 2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy3,4-difluoro-benzamide], and U0126 [ 1,4-diamino-2,3-dicyano-1,4-bis( 2- aminophenylthio) butadiene] all produced concentration-dependent suppression of the proliferation of the three cell lines. Individual MEK inhibitors had similar effects in all three cell lines. However, only the antiproliferative effects of PD184352 correlated closely with the elimination of ERK1,2 MAP kinase activities. PD98059 was primarily cytostatic, whereas U0126 and PD184352 were cytotoxic. Only PD184352 induced apoptosis in all three lines, as indicated by morphology, activation of DEVDase, procaspase-3 cleavage, and the appearance of populations having sub-G(0)/G(1) DNA contents. The differential effects of the MEK inhibitors on cell survival were not dependent on p53 status or effects on the ERK5 pathway. PD184352 was also proapoptotic to primary rat Schwann cells. Hence, although PD184352 effectively killed neurofibrosarcoma cells, its effects on normal Schwann cells may limit its usefulness in the clinic.