Abstract：
Breast cancer is one of the most common cancers globally and a leading cause of cancer-related deaths among women. Despite the combination of chemotherapy with targeted therapy, including monoclonal antibodies and kinase inhibitors, drug resistance and treatment failure remain a common occurrence. Copper, complexed to various organic ligands, has gained attention as potential chemotherapeutic agents due to its perceived decreased toxicity to normal cells. The cytotoxic efficacy and the mechanism of cell death of an 8-aminoquinoline-naphthyl copper complex (Cu8AqN) in MCF-7 and MDA-MB-231 breast cancer cell lines was investigated. The complex inhibited the growth of MCF-7 and MDA-MB-231 cells with IC50 values of 2.54 ± 0.69 μM and 3.31 ± 0.06 μM, respectively. Nuclear fragmentation, annexin V binding, and increased caspse-3/7 activity indicated apoptotic cell death. The loss of mitochondrial membrane potential, an increase in caspase-9 activity, the absence of active caspase-8 and a decrease of tumour necrosis factor receptor 1(TNFR1) expression supported activation of the intrinsic apoptotic pathway. Increased ROS formation and increased expression of haem oxygenase-1 (HMOX-1) indicated activation of cellular stress pathways. Expression of p21 protein in the nuclei was increasedindicating cell cycle arrest, whilst the expression of inhibitor of apoptosis proteins (IAPs), cIAP1, XIAP and survivin were decreased creating a pro-apoptotic environment. Phosphorylated p53 species; phospho-p53(S15), phospho-p53(S46), and phospho-p53(S392) accumulated in MCF-7 cells indicating the potential of Cu8AqN to restore p53 function in the cells. In combination, the data indicates that Cu8AqN is a useful lead molecule worthy of further exploration as a potential anti-cancer drug.
摘要：
乳腺癌是全球最常见的癌症之一，也是女性癌症相关死亡的主要原因。尽管化疗与靶向治疗相结合，包括单克隆抗体和激酶抑制剂，耐药和治疗失败仍然很常见。铜,络合到各种有机配体，作为潜在的化学治疗剂，由于其对正常细胞的毒性降低而受到关注。研究了MCF-7和MDA-MB-231乳腺癌细胞系中8-氨基喹啉-萘基铜复合物（Cu8AqN）的细胞毒性功效和细胞死亡机制。该复合物抑制MCF-7和MDA-MB-231细胞的生长，IC50值分别为2.54±0.69μM和3.31±0.06μM，分别。核分裂,膜联蛋白V结合，caspse-3/7活性增加表明凋亡性细胞死亡。线粒体膜电位的丧失,caspase-9活性增加，活性caspase-8的缺失和肿瘤坏死因子受体1（TNFR1）表达的降低支持了内在凋亡途径的激活。增加的ROS形成和血红素加氧酶-1（HMOX-1）的表达增加表明细胞应激途径的激活。p21蛋白在细胞核中的表达增加，表明细胞周期停滞，而凋亡抑制蛋白（IAP）的表达，cIAP1，XIAP和survivin降低，从而产生促凋亡环境。磷酸化p53种类;磷酸-p53(S15),磷酸化p53(S46),和磷酸化p53(S392)在MCF-7细胞中积累,表明Cu8AqN在细胞中恢复p53功能的潜力。在组合中，数据表明，Cu8AqN是一种有用的先导分子，作为潜在的抗癌药物值得进一步探索。
