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A novel binuclear hydrazone-based Cd(II) complex is a strong pro-apoptotic inducer with significant activity against 2D and 3D pancreatic cancer stem cells.
Journal of Inorganic Biochemistry ( IF 3.8 ) Pub Date : 2018-10-14 , DOI: 10.1016/j.jinorgbio.2018.10.002
Snežana Bjelogrlić 1 , Tamara R Todorović 2 , Ilija Cvijetić 3 , Marko V Rodić 4 , Miroslava Vujčić 5 , Sanja Marković 2 , Jovana Araškov 2 , Barbara Janović 5 , Fathi Emhemmed 6 , Christian D Muller 6 , Nenad R Filipović 7
Affiliation  

A novel binuclear Cd complex (1) with hydrazone-based ligand was prepared and characterized by spectroscopy and single crystal X-ray diffraction techniques. Complex 1 reveals a strong pro-apoptotic activity in both human, mammary adenocarcinoma cells (MCF-7) and pancreatic AsPC-1 cancer stem cells (CSCs). While apoptosis undergoes mostly caspase-independent, 1 stimulates the activation of intrinsic pathway with noteworthy down regulation of caspase-8 activity in respect to non-treated controls. Distribution of cells over mitotic division indicates that 1 caused DNA damage in both cell lines, which is confirmed in DNA interaction studies. Compared to 1, cisplatin (CDDP) does not achieve cell death in 2D cultured AsPC-1 cells, while induces different pattern of cell cycle changes and caspase activation in 2D cultured MCF-7 cells, implying that these two compounds do not share similar mechanism of action. Additionally, 1 acts as a powerful inducer of mitochondrial superoxide production with dissipated trans-membrane potential in the majority of the treated cells already after 6 h of incubation. On 3D tumors, 1 displays a superior activity against CSC model, and at 100 μM induces disintegration of spheroids within 2 days of incubation. Fluorescence spectroscopy, along with molecular docking show that compound 1 binds to the minor groove of DNA. Compound 1 binds to the human serum albumin (HSA) showing that the HSA can effectively transport and store 1 in the human body. Thus, our current study strongly supports further investigations on antitumor activity of 1 as a drug candidate for the treatment of highly resistant pancreatic cancer.

中文翻译:

一种新型的基于双的Cd(II)复合物是一种强大的促凋亡诱导剂,对2D和3D胰腺癌干细胞具有显着的活性。

制备了具有基配体的新型双核Cd配合物(1),并通过光谱学和单晶X射线衍射技术对其进行了表征。复合物1在人乳腺腺癌细胞(MCF-7)和胰腺AsPC-1癌症干细胞(CSC)中均显示出强大的促凋亡活性。虽然凋亡主要经历caspase依赖性,但1刺激内在途径的激活,与未处理的对照组相比,caspase-8活性显着下调。细胞在有丝分裂分裂中的分布表明1在两种细胞系中均引起DNA损伤,这在DNA相互作用研究中得到了证实。与1相比,顺铂(CDDP)在2D培养的AsPC-1细胞中未实现细胞死亡,而在2D培养的MCF-7细胞中诱导了不同的细胞周期变化和caspase激活模式,暗示这两种化合物不具有相似的作用机理。此外,在孵育6小时后,大多数处理过的细胞中,1充当了线粒体超氧化物产生的强大诱导物,并且具有消散的跨膜电位。在3D肿瘤上,1显示出对CSC模型的优越活性,并且在孵育2天之内,以100μM的剂量诱导球体崩解。荧光光谱以及分子对接表明化合物1与DNA的小沟结合。化合物1与人血清白蛋白(HSA)结合,表明HSA可以在人体中有效运输和储存1。因此,我们目前的研究强烈支持进一步研究1作为治疗高耐药性胰腺癌的候选药物的抗肿瘤活性。
更新日期:2018-10-14
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