Abu-Serie Marwa M, Blasco María A
Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Egypt.
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain.
Nanomedicine (Lond). 2025 Jun;20(11):1267-1280. doi: 10.1080/17435889.2025.2502321. Epub 2025 May 16.
Targeting cancer stem cells (CSCs)-mediated aggressive features of non-small cell lung cancer (NSCLC) is a promising anticancer approach. This can be accomplished via suppressing critical mediators, such as functional mitochondria, aldehyde dehydrogenase (ALDH)1A, and telomere protectors (telomerase reverse transcriptase (TERT) and telomere repeat binding factor (TRF)1).
MATERIALS & METHODS: Copper nanocomplexes (diethyldithiocarbamate (DE)-CuO nanoparticles (NPs) and DE-Cu NPs) were prepared using the simplest green chemistry method and assessed for inducing mitochondrial dysfunction-dependent non-apoptotic pathway (cuproptosis) and repressing CSC markers.
DE-CuO NPs had higher growth inhibition for NSCLC (A549, H520, and H1299) spheroids than DE-Cu NPs. DE-CuO NPs had higher uptake rate and prooxidant effect resulting in lower mitochondrial membrane potential and mitochondrial DNA copy number, as well as stronger inhibition of telomerase and ALDH1A than DE-Cu NPs. This caused dramatic redox imbalance and lowering AKT pathway (activator of telomere stabilizers and stemness)-mediated repression of TERT and TRF1 protein levels as well as phosphorylated NF-κB subunit (p65) led to collapsing telomeres, as evidenced by downregulating TERT regulators and confocal microscopy. In animal study, this active nanocomplex revealed powerful and selective therapeutic tumor-targeting effects, with no evidence of toxicity to healthy tissues.
DE-CuO nanocomplex is deemed as promising nanomedicine for NSCLC.
靶向癌症干细胞（CSCs）介导的非小细胞肺癌（NSCLC）侵袭性特征是一种很有前景的抗癌方法。这可以通过抑制关键介质来实现，如功能性线粒体、醛脱氢酶（ALDH）1A和端粒保护因子（端粒酶逆转录酶（TERT）和端粒重复结合因子（TRF）1）。
采用最简单的绿色化学方法制备铜纳米复合物（二乙基二硫代氨基甲酸盐（DE）-氧化铜纳米颗粒（NPs）和DE-铜纳米颗粒），并评估其诱导线粒体功能障碍依赖性非凋亡途径（铜死亡）和抑制CSC标志物的能力。
DE-氧化铜纳米颗粒对NSCLC（A549、H520和H1299）球体的生长抑制作用高于DE-铜纳米颗粒。DE-氧化铜纳米颗粒具有更高的摄取率和促氧化作用，导致线粒体膜电位和线粒体DNA拷贝数降低，并且对端粒酶和ALDH1A的抑制作用比DE-铜纳米颗粒更强。这导致了显著的氧化还原失衡，并降低了AKT途径（端粒稳定剂和干性激活剂）介导的TERT和TRF1蛋白水平的抑制，以及磷酸化的NF-κB亚基（p65）导致端粒崩溃，这通过下调TERT调节因子和共聚焦显微镜得到证实。在动物研究中，这种活性纳米复合物显示出强大且选择性的治疗性肿瘤靶向作用，没有对健康组织产生毒性的证据。
DE-氧化铜纳米复合物被认为是一种有前景的NSCLC纳米药物。
