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Cuprous oxide nanoparticles trigger ER stress-induced apoptosis by regulating copper trafficking and overcoming resistance to sunitinib therapy in renal cancer
Biomaterials ( IF 14.0 ) Pub Date : 2017-09-05 , DOI: 10.1016/j.biomaterials.2017.09.008
Qiwei Yang , Ye Wang , Qing Yang , Yi Gao , Xiaopeng Duan , Qingcheng Fu , Chuanmin Chu , Xiuwu Pan , Xingang Cui , Yinghao Sun

While the current standard first-line treatment for advanced renal cell carcinoma (RCC) is sunitinib, patients inevitably develop resistance to this drug. However, the rapid development of nanotechnology has provided emerging techniques for the treatment of advanced tumours, including RCC. In our previous research, cuprous oxide nanoparticles (CONPs) showed ideal anti-tumour effects and low systemic toxicity. While many inorganic nanomedicines, including CONPs, have similar pharmacological effects, their detailed mechanisms remain unknown. Copper chaperone proteins, which regulate the endocellular dosage and transport of copper, also play crucial roles in the progression of cancer. In this research, we discovered that CONPs can disrupt copper transportation by regulating the copper chaperone proteins ATOX1 and CCS in RCC cells and induce endoplasmic reticulum (ER) stress in vitro and in vivo by promoting the accumulation of intracellular calcium and reactive oxygen species (ROS). Furthermore, CONPs can initiate ER- and mitochondrial-dependent apoptosis by activating caspase-3, caspase-9 and caspase-12. In addition, CONPs downregulate the expression of AXL, MET, AKT, and ERK to recover sunitinib responsiveness in RCC cells with sunitinib resistance (SR) and may therefore facilitate the development of promising new pathways to treat patients with acquired SRRCC.

中文翻译:

氧化亚铜纳米颗粒通过调节铜的运输并克服对肾癌舒尼替尼治疗的耐药性来触发内质网应激诱导的细胞凋亡

尽管目前用于晚期肾细胞癌(RCC)的标准一线治疗是舒尼替尼,但患者不可避免地会对这种药物产生耐药性。但是,纳米技术的飞速发展为包括RCC在内的晚期肿瘤的治疗提供了新兴技术。在我们之前的研究中,氧化亚铜纳米颗粒(CONPs)具有理想的抗肿瘤作用和低全身毒性。尽管许多无机纳米药物(包括CONPs)具有相似的药理作用,但其详细机理仍然未知。铜伴侣蛋白,调节铜的胞内剂量和运输,在癌症的进展中也起着关键作用。在这项研究中 我们发现CONPs可以通过调节RCC细胞中的铜伴侣蛋白ATOX1和CCS破坏铜的运输,并通过促进细胞内钙和活性氧(ROS)的积累在体内和体外诱导内质网(ER)应激。此外,CONPs可以通过激活caspase-3,caspase-9和caspase-12来启动ER和线粒体依赖性细胞凋亡。此外,CONP下调AXL,MET,AKT和ERK的表达,以恢复具有舒尼替尼耐药性(SR)的RCC细胞中舒尼替尼的反应性,因此可能有助于开发有前途的新途径来治疗获得性SRRCC的患者。CONPs可以通过激活caspase-3,caspase-9和caspase-12来启动ER和线粒体依赖性细胞凋亡。此外,CONP下调AXL,MET,AKT和ERK的表达,以恢复具有舒尼替尼耐药性(SR)的RCC细胞中舒尼替尼的反应性,因此可能有助于开发有前途的新途径来治疗获得性SRRCC的患者。CONPs可以通过激活caspase-3,caspase-9和caspase-12来启动ER和线粒体依赖性细胞凋亡。此外,CONP下调AXL,MET,AKT和ERK的表达,以恢复具有舒尼替尼耐药性(SR)的RCC细胞中舒尼替尼的反应性,因此可能有助于开发有前途的新途径来治疗获得性SRRCC的患者。
更新日期:2017-09-05
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