Mármol Inés, Virumbrales-Muñoz María, Quero Javier, Sánchez-de-Diego Cristina, Fernández Luis, Ochoa Ignacio, Cerrada Elena, Yoldi Mª Jesús Rodríguez
Department of Pharmacology and Physiology, University of Zaragoza, CIBERobn, IIS Aragón, IA2, Zaragoza, Spain.
Group of Applied Mechanics and Bioengineering (AMB), University of Zaragoza, CIBER-BBN, I3A, Aragon Institute of Biomedical Research, Zaragoza, Spain.
J Inorg Biochem. 2017 Nov;176:123-133. doi: 10.1016/j.jinorgbio.2017.08.020. Epub 2017 Aug 31.
Given the rise of apoptosis-resistant tumors, there exist a growing interest in developing new drugs capable of inducing different types of cell death to reduce colorectal cancer-related death rates. As apoptosis and necroptosis do not share cellular machinery, necroptosis induction may have a great therapeutic potential on those apoptosis-resistant cancers, despite the inflammatory effects associated with it. We have synthesized an alkynyl gold(I) complex [Au(CC-2-NCH)(PTA)] whose anticancer effect was tested on the colorectal adenocarcinoma Caco-2 cell line. With regard to its mechanism of action, this gold complex enters the mitochondria and disrupts its normal function, leading to an increase in ROS production, which triggers necroptosis. Necroptosis induction has been found dependent of TNF-α (Tumor necrosisfactor α) and TNFR1(Tumor necrosisfactor receptor 1) binding, RIP1(Receptor-Interacting Protein 1) activation and NF-κB (Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells) signaling. Moreover, the antitumor potential of [Au(CC-2-NCH)(PTA)] has also been confirmed on the 3D cancer model spheroid. Overall, the obtained data show firstly that gold complexes might have the ability of inducing necroptosis, and secondarily that our compound [Au(CC-2-NCH)(PTA)] is an interesting alternative to current chemotherapy drugs in cases of apoptosis resistance.
鉴于抗凋亡肿瘤的增多，人们对开发能够诱导不同类型细胞死亡以降低结直肠癌相关死亡率的新药的兴趣日益浓厚。由于凋亡和坏死性凋亡不共享细胞机制，尽管存在与之相关的炎症效应，但诱导坏死性凋亡可能对那些抗凋亡癌症具有巨大的治疗潜力。我们合成了一种炔基金（I）配合物[Au(CC-2-NCH)(PTA)]，并在结直肠腺癌Caco-2细胞系上测试了其抗癌效果。关于其作用机制，这种金配合物进入线粒体并破坏其正常功能，导致活性氧生成增加，从而触发坏死性凋亡。已发现诱导坏死性凋亡依赖于肿瘤坏死因子α（TNF-α）和肿瘤坏死因子受体1（TNFR1）的结合、受体相互作用蛋白1（RIP1）的激活以及核因子κB（NF-κB）信号传导。此外，[Au(CC-2-NCH)(PTA)]在3D癌症模型球体上的抗肿瘤潜力也得到了证实。总体而言，获得的数据首先表明金配合物可能具有诱导坏死性凋亡的能力，其次表明在凋亡抵抗的情况下，我们的化合物[Au(CC-2-NCH)(PTA)]是当前化疗药物的一个有趣替代品。
