Liu Jie, Malavya Swati, Wang Xueqian, Saavedra Joseph E, Keefer Larry K, Tokar Erik, Qu Wei, Waalkes Michael P, Shami Paul J
Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Research Triangle Park, NC, USA.
Genomics. 2009 Jul;94(1):32-8. doi: 10.1016/j.ygeno.2009.03.005. Epub 2009 Apr 5.
The nitric oxide (NO) prodrug JS-K is shown to have anticancer activity. To profile the molecular events associated with the anticancer effects of JS-K, HL-60 leukemia cells were treated with JS-K and subjected to microarray and real-time RT-PCR analysis. JS-K induced concentration- and time-dependent gene expression changes in HL-60 cells corresponding to the cytolethality effects. The apoptotic genes (caspases, Bax, and TNF-alpha) were induced, and differentiation-related genes (CD14, ITGAM, and VIM) were increased. For acute phase protein genes, some were increased (TP53, JUN) while others were suppressed (c-myc, cyclin E). The expression of anti-angiogenesis genes THBS1 and CD36 and genes involved in tumor cell migration such as tissue inhibitors of metalloproteinases, were also increased by JS-K. Confocal analysis confirmed key gene changes at the protein levels. Thus, multiple molecular events are associated with JS-K effects in killing HL-60, which could be molecular targets for this novel anticancer NO prodrug.
一氧化氮（NO）前药JS-K已被证明具有抗癌活性。为了剖析与JS-K抗癌作用相关的分子事件，用JS-K处理HL-60白血病细胞，并进行微阵列和实时逆转录聚合酶链反应分析。JS-K在HL-60细胞中诱导了与细胞致死效应相对应的浓度和时间依赖性基因表达变化。凋亡基因（半胱天冬酶、Bax和肿瘤坏死因子-α）被诱导，与分化相关的基因（CD14、整合素αM和波形蛋白）增加。对于急性期蛋白基因，一些基因增加（TP53、JUN），而另一些基因被抑制（c-myc、细胞周期蛋白E）。JS-K还增加了抗血管生成基因THBS1和CD36以及参与肿瘤细胞迁移的基因（如金属蛋白酶组织抑制剂）的表达。共聚焦分析证实了关键基因在蛋白水平上的变化。因此，多种分子事件与JS-K杀伤HL-60细胞的作用相关，这些事件可能是这种新型抗癌NO前药的分子靶点。
