Bithionol 通过抑制 NF-κB 信号传导和诱导氧化应激来消除急性髓系白血病干样细胞，从而导致细胞凋亡和铁死亡。
Bithionol eliminates acute myeloid leukaemia stem-like cells by suppressing NF-κB signalling and inducing oxidative stress, leading to apoptosis and ferroptosis.
发表日期：2024 Aug 29
作者：
Ingrid R S B Dias, Rafaela G A Costa, Ana Carolina B da C Rodrigues, Suellen L R Silva, Maiara de S Oliveira, Milena B P Soares, Rosane B Dias, Ludmila F Valverde, Clarissa A Gurgel Rocha, Lauren V Cairns, Ken I Mills, Daniel P Bezerra
来源：
Alzheimers & Dementia
摘要：
急性髓系白血病 (AML) 是一种由血细胞祖细胞基因改变引起的致命性骨髓肿瘤。白血病干细胞 (LSC) 与 AML 的发生、耐药性和复发有关。 Bithionol 是一种古老的驱虫药，具有潜在的抗菌、抗病毒、抗真菌、抗阿尔茨海默病和抗肿瘤特性。在这项工作中，我们重点研究了联硫醇的抗 AML LSC 特性。该化合物在 50 mg/kg 剂量下可抑制实体癌细胞和血液癌细胞的活力，抑制 AML 干细胞样细胞，并抑制 NSG 小鼠的 AML 生长，且具有可耐受的全身毒性。 Bithionol 显着降低 AML 细胞中磷酸 NF-κB p65 (Ser529) 和磷酸 NF-κB p65 (Ser536) 的水平以及核 NF-κB p65 易位，表明该分子可以抑制 NF-κB 信号传导。在联硫醇处理的 AML 细胞中检测到 DNA 断裂、核浓缩、细胞收缩、磷脂酰丝氨酸外化、跨膜线粒体电位丧失、caspase-3 激活和 PARP-(Asp 214) 裂解，表明诱导了细胞凋亡。此外，该化合物增加了线粒体超氧化物水平，并且通过与选择性铁死亡抑制剂 Ferrostatin-1 共同处理，部分阻止了联硫醇诱导的细胞死亡，表明铁死亡的诱导。此外，在 AML 细胞中，联硫醇与维奈托克具有协同作用，表明联硫醇具有增强维奈托克对 AML 患者疗效的转化潜力。总而言之，这些数据表明 bithionol 是一种潜在的新型抗 AML 药物。© 2024。作者。
Acute myeloid leukaemia (AML) is a lethal bone marrow neoplasm caused by genetic alterations in blood cell progenitors. Leukaemic stem cells (LSCs) are responsible for the development of AML, drug resistance and relapse. Bithionol is an old anthelmintic drug with potential antibacterial, antiviral, antifungal, anti-Alzheimer, and antitumour properties. In this work, we focused on the anti-AML LSC properties of bithionol. This compound inhibited the viability of both solid and haematological cancer cells, suppressed AML stem-like cells, and inhibited AML growth in NSG mice at a dosage of 50 mg/kg, with tolerable systemic toxicity. Bithionol significantly reduced the levels of phospho-NF-κB p65 (Ser529) and phospho-NF-κB p65 (Ser536) and nuclear NF-κB p65 translocation in AML cells, indicating that this molecule can suppress NF-κB signalling. DNA fragmentation, nuclear condensation, cell shrinkage, phosphatidylserine externalisation, loss of transmembrane mitochondrial potential, caspase-3 activation and PARP-(Asp 214) cleavage were detected in bithionol-treated AML cells, indicating the induction of apoptosis. Furthermore, this compound increased mitochondrial superoxide levels, and bithionol-induced cell death was partially prevented by cotreatment with the selective ferroptosis inhibitor ferrostatin-1, indicating the induction of ferroptosis. In addition, bithionol synergised with venetoclax in AML cells, indicating the translational potential of bithionol to enhance the effects of venetoclax in patients with AML. Taken together, these data indicate that bithionol is a potential new anti-AML drug.© 2024. The Author(s).