Human ovarian cancer stem cells (HuOCSCs) are the main source of ovarian cancer recurrence, metastasis, and drug resistance. Superparamagnetic iron oxide nanoparticles (SPIONs) are well-known nucleic acid or drug carriers owing to their controllable properties, superior stability, and easy modification. However, whether SPIONs can inhibit the activity of HuOCSCs by inducing ferroptosis remains unclear. In the present study, we isolated CD44⁺ /CD133⁺ HuOCSCs from tumours of four patients with clear cell ovarian cancer and added 0.2 mM SPIONs for mixed culture. Transmission electron microscopy showed that SPION-treated HuOCSCs contained multiple high-density electron clouds. Prussian blue staining showed high concentrations of iron ions in the cells. In vitro , SPIONs treatment of HuOCSCs inhibited cell proliferation, migration, and soft agar clone formation, weakened their resistance to multiple chemotherapeutics, and induced cell death. In vivo , SPIONs pretreatment of HuOCSCs significantly reduced their tumour-forming ability and induced angiogenesis in nude mice. Further, SPIONs induced the accumulation of reactive oxygen species in HuOCSCs and induced oxidative stress. qPCR analysis indicated that SPIONs-treated HuOCSCs had reduced expression of tumour stem cell markers (CD117, NANOG, CD133, and SOX2), cell proliferation factors (KI67, CCND), autophagy-related factors (ATG3, ATG5, MAP1ALC3a, MAP1ALC3b, and MAP1ALC3c), and certain negative regulators of ferroptosis, while the mRNA expression levels of cell death-related proteins (BAK1 and BID), and certain positive regulators of ferroptosis were significantly increased. Overall, our findings suggest that SPIONs induce oxidative stress and decrease autophagy activity in ovarian cancer stem cells, activate ferroptosis, and inhibit their proliferation, invasion, drug resistance, and tumorigenic ability.

中文翻译：

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超顺磁性氧化铁纳米粒子通过减弱细胞自噬作用诱导人类卵巢癌干细胞的肥大病。

人卵巢癌干细胞（HuOCSC）是卵巢癌复发，转移和耐药性的主要来源。超顺磁性氧化铁纳米粒子（SPIONs）由于其可控制的特性，出色的稳定性和易于修饰而成为众所周知的核酸或药物载体。但是，尚不清楚SPIONs是否可以通过诱导肥大作用来抑制HuOCSCs的活性。在本研究中，我们分离出CD44 ⁺ / CD133 ⁺来自四名患有透明细胞卵巢癌的患者的肿瘤中的HuOCSC，并添加了0.2 mM SPION用于混合培养。透射电子显微镜显示，经SPION处理的HuOCSCs包含多个高密度电子云。普鲁士蓝染色显示细胞中高浓度的铁离子。在体外，用SPIONs处理的HuOCSC抑制了细胞增殖，迁移和软琼脂克隆的形成，削弱了其对多种化学疗法的抵抗力，并诱导了细胞死亡。在体内，HuOCSC的SPION预处理显着降低了它们的肿瘤形成能力并诱导了裸鼠的血管生成。此外，SPIONs诱导了HuOCSCs中活性氧物种的积累并诱导了氧化应激。qPCR分析表明，经SPIONs处理的HuOCSCs降低了肿瘤干细胞标记物（CD117，NANOG，CD133和SOX2），细胞增殖因子（KI67，CCND），自噬相关因子（ATG3，ATG5，MAP1ALC3a，MAP1ALC3b和MAP1ALC3c）以及某些受精卵的负调控因子，而细胞死亡相关蛋白的mRNA表达水平（BAK1和BID），以及某些特定的铁质调节阳性调节剂。总体而言，我们的发现表明SPIONs可以诱导氧化应激并降低卵巢癌干细胞的自噬活性，激活肥大症，并抑制其增殖，侵袭，耐药性和致瘤能力。某些铁素体调节阳性调节剂明显增加。总体而言，我们的发现表明SPIONs可以诱导氧化应激并降低卵巢癌干细胞的自噬活性，激活肥大症，并抑制其增殖，侵袭，耐药性和致瘤能力。某些铁素体调节阳性调节剂明显增加。总体而言，我们的发现表明SPIONs可以诱导氧化应激并降低卵巢癌干细胞的自噬活性，激活肥大症，并抑制其增殖，侵袭，耐药性和致瘤能力。