Department of Experimental Therapeutics, Center for RNAi and non-coding-RNA, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Clin Cancer Res. 2010 Jan 1;16(1):184-94. doi: 10.1158/1078-0432.CCR-09-1180. Epub 2009 Dec 22.
To show the functional, clinical, and biological significance of c-Jun-NH(2)-kinase (JNK)-1 in ovarian carcinoma.
Analysis of the impact of JNK on 116 epithelial ovarian cancers was conducted. The role of JNK in vitro and in experimental models of ovarian cancer was assessed. We studied the role of N-5-[4-(4-methyl piperazine methyl)-benzoylamido]-2-methylphenyl-4-[3-(4-methyl)-pyridyl]-2-pyrimidine amine (WBZ_4), a novel JNK inhibitor redesigned from imatinib based on targeting wrapping defects, in cell lines and in experimental models of ovarian cancer.
We found a significant association of pJNK with progression-free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose-dependent fashion in four ovarian cancer cell lines. In vivo, whereas imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The antitumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights compared with nonsilencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition.
These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the redesigned WBZ_4 compound should be considered for further clinical development.
展示 c-Jun-NH(2)-kinase（JNK）-1 在卵巢癌中的功能、临床和生物学意义。
分析了 JNK 对 116 例上皮性卵巢癌的影响。评估了 JNK 在体外和卵巢癌实验模型中的作用。我们研究了 N-5-[4-(4-甲基哌嗪甲基)苯甲酰胺基]-2-甲基苯基-4-[3-(4-甲基)-吡啶基]-2-嘧啶胺（WBZ_4）的作用，这是一种基于针对包裹缺陷的重新设计的新型 JNK 抑制剂，从伊马替尼衍生而来，用于细胞系和卵巢癌实验模型。
我们发现，在初次减瘤治疗时获得的 116 例上皮性卵巢癌中，pJNK 与无进展生存期显著相关。WBZ_4 以剂量依赖性方式导致四种卵巢癌细胞系的细胞生长抑制和凋亡增加。在体内，虽然伊马替尼对肿瘤生长没有影响，但 WBZ_4 抑制了卵巢癌的原位小鼠模型中的肿瘤生长。与多西他赛联合使用时，抗肿瘤效果进一步增加。与非沉默 siRNA 对照相比，系统给予的 JNK-1 siRNA 导致肿瘤重量明显减轻，这表明观察到的抗肿瘤作用确实是由于 JNK-1 抑制所致。
这些研究将 JNK-1 确定为卵巢癌有吸引力的治疗靶标，并且重新设计的 WBZ_4 化合物应考虑进一步的临床开发。
