Sorriento D, Del Giudice C, Bertamino A, Ciccarelli M, Gomez-Monterrey I, Campiglia P, Novellino E, Illario M, Trimarco B, De Luca N, Iaccarino G
1] Department of Advanced Biomedical Sciences, 'Federico II' University of Naples, Naples 80131, Italy [2] Institute of Biostructure and Bioimaging (IBB) of the Italian National Research Council (CNR), Naples 80145, Italy.
Department of Advanced Biomedical Sciences, 'Federico II' University of Naples, Naples 80131, Italy.
Br J Cancer. 2015 Jan 6;112(1):77-85. doi: 10.1038/bjc.2014.577. Epub 2014 Nov 25.
p53 is a transcription factor with tumour suppressor properties, which is able to induce mitochondrial apoptosis independently of its transcriptional activity. We recently synthesised two new compounds (ISA27 and SM13), which block p53-MDM2 interaction and induce apoptosis in p53 wild-type (WT) tumour cells. The aim of this study was to verify the effectiveness of these compounds in tumours carrying a mutated form of p53 gene with no transcriptional activity.
In vitro we evaluated the effectiveness of our compounds in cancer cell lines carrying WT, mutated and null p53 gene. In vivo study was performed in Balb/c nude mice and the mitochondrial-dependent apoptotic signalling was evaluated by western blot.
Both ISA27 and SM13 reduced cell proliferation and induced apoptosis in vitro in cells carrying either p53 WT or mutated gene, suggesting that its effect is independent from p53 transcriptional activity. On the contrary, SM13 had no effect in a p53 null cell line. In vivo, ISA27 and SM13 induced cancer cell death in a dose-dependent manner through the activation of the mitochondrial-dependent death signalling in p53-mutated cells. In vivo, SM13 reduced tumour growth.
Our study proposes SM13 as anticancer compound to use for the treatment of p53-dependent tumours, even in the absence of p53 transcriptional activity.
p53是一种具有肿瘤抑制特性的转录因子，能够独立于其转录活性诱导线粒体凋亡。我们最近合成了两种新化合物（ISA27和SM13），它们可阻断p53-MDM2相互作用并在p53野生型（WT）肿瘤细胞中诱导凋亡。本研究的目的是验证这些化合物在携带无转录活性的p53基因变异形式的肿瘤中的有效性。
在体外，我们评估了我们的化合物在携带WT、突变和无p53基因的癌细胞系中的有效性。在Balb/c裸鼠中进行体内研究，并通过蛋白质印迹法评估线粒体依赖性凋亡信号传导。
ISA27和SM13在体外均可降低携带p53 WT或突变基因的细胞的增殖并诱导凋亡，这表明其作用独立于p53转录活性。相反，SM13在p53缺失的细胞系中没有作用。在体内，ISA27和SM13通过激活p53突变细胞中的线粒体依赖性死亡信号以剂量依赖性方式诱导癌细胞死亡。在体内，SM13可降低肿瘤生长。
我们的研究提出将SM13作为抗癌化合物用于治疗p53依赖性肿瘤，即使在没有p53转录活性的情况下。
