Allam Rasha M, El-Nasr Nesma M E Abo, Elbaset Marawan A, Saleh Dalia O, El-Seidy Ahmed M A
Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, P.O. 12622, Cairo, Egypt.
Inorganic Chemistry Department, Advanced Materials Technology & Mineral Resources Research Institute, National Research Centre, P.O. 12622, Dokki, Cairo, Egypt.
Sci Rep. 2025 May 3;15(1):15477. doi: 10.1038/s41598-025-97395-4.
Human hepatocellular carcinoma (HCC) is recognized as one of the leading causes of death globally and is resistant to several anticancer drugs. As a result, it is critical to identify more effective druggable therapies. Metal oxide nanoparticles (MO-NPs), especially nanocomposites, have recently received much attention owing to their potential applications in cancer therapy. In this study, we synthesized zinc oxide (ZnO) and copper oxide (CuO) nanocomposites in different ratios (N1, N2, and N3). We evaluated their cytotoxicity against two HCC cell lines (HepG2 and HuH-7) and one normal liver cell (BNL), compared with Sorafenib as a standard therapy. Then, we investigated the potential underlying mechanisms of anticancer action employing flow cytometry, migration assay, and western blot. The results showed that the nanocomposite with an equal ratio of both ZnO and CuO-NPs (N1) exhibited the highest cytotoxic activity on the HuH7 cell line while exerting no detrimental impact on normal rat liver epithelial cells. Further investigation into the toxicity mechanisms of N1 revealed three modalities of induced cell death (apoptotic, necrotic, and autophagic) along with S- and G2/M cell cycle arrest, suggesting mitotic catastrophe. Furthermore, N1 displayed potent anti-migratory activity, surpassing sorafenib, upregulated the protein level of autophagy marker beclin-1, while downregulated the protein level of EMT-marker vimentin. Overall, our findings showed that combining ZnO-NPs and CuO-NPs is more intriguing in combating HCC, providing prospective guidance for evolving liver cancer therapy employing bimetallic NPs.
人类肝细胞癌（HCC）是全球主要死因之一，并且对多种抗癌药物具有抗性。因此，确定更有效的可药物治疗方法至关重要。金属氧化物纳米颗粒（MO-NPs），尤其是纳米复合材料，由于其在癌症治疗中的潜在应用，最近受到了广泛关注。在本研究中，我们合成了不同比例（N1、N2和N3）的氧化锌（ZnO）和氧化铜（CuO）纳米复合材料。我们评估了它们对两种肝癌细胞系（HepG2和HuH-7）和一种正常肝细胞（BNL）的细胞毒性，并与作为标准疗法的索拉非尼进行了比较。然后，我们采用流式细胞术、迁移试验和蛋白质印迹法研究了抗癌作用的潜在机制。结果表明，ZnO和CuO-NPs比例相等的纳米复合材料（N1）对HuH7细胞系表现出最高的细胞毒性活性，同时对正常大鼠肝上皮细胞没有不利影响。对N1毒性机制的进一步研究揭示了诱导细胞死亡的三种方式（凋亡、坏死和自噬）以及S期和G2/M期细胞周期阻滞，提示有丝分裂灾难。此外，N1表现出强大的抗迁移活性，超过索拉非尼，上调自噬标志物beclin-1的蛋白水平，同时下调EMT标志物波形蛋白的蛋白水平。总体而言，我们的研究结果表明，将ZnO-NPs和CuO-NPs结合起来在对抗HCC方面更具吸引力，为采用双金属NP发展肝癌治疗提供了前瞻性指导。
