LoBianco Francesca V, Krager Kimberly J, Johnson Erica, Godwin Christopher O, Allen Antino R, Crooks Peter A, Compadre Cesar M, Borrelli Michael J, Aykin-Burns Nukhet
Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Front Toxicol. 2022 Dec 14;4:936149. doi: 10.3389/ftox.2022.936149. eCollection 2022.
Hepatocellular carcinoma (HCC) is both a devastating and common disease. Every year in the United States, about 24,500 men and 10,000 women are diagnosed with HCC, and more than half of those diagnosed patients die from this disease. Thus far, conventional therapeutics have not been successful for patients with HCC due to various underlying comorbidities. Poor survival rate and high incidence of recurrence after therapy indicate that the differences between the redox environments of normal surrounding liver and HCC are valuable targets to improve treatment efficacy. Parthenolide (PTL) is a naturally found therapeutic with anti-cancer and anti-inflammatory properties. PTL can alter HCC's antioxidant environment through thiol modifications leaving tumor cells sensitive to elevated reactive oxygen species (ROS). Investigating the link between altered thiol mechanism and increased sensitivity to iron-mediated lipid peroxidation will allow for improved treatment of HCC. HepG2 (human) and McARH7777 (rat) HCC cells treated with PTL with increasing concentrations decrease cell viability and clonogenic efficiency . PTL increases glutathione (GSH) oxidation rescued by the addition of a GSH precursor, N-acetylcysteine (NAC). In addition, this elevation in thiol oxidation results in an overall increase in mitochondrial dysfunction. To elucidate if cell death is through lipid peroxidation, using a lipid peroxidation sensor indicated PTL increases lipid oxidation levels after 6 h. Additionally, western blotting reveals glutathione peroxidase 4 (GPx4) protein levels decrease after treatment with PTL suggesting cells are incapable of preventing lipid peroxidation after exposure to PTL. An elevation in lipid peroxidation will lead to a form of cell death known as ferroptosis. To further establish ferroptosis as a critical mechanism of death for HCC , the addition of ferrostatin-1 combined with PTL demonstrates a partial recovery in a colony survival assay. This study reveals that PTL can induce tumor cell death through elevations in intracellular oxidation, leaving cells sensitive to ferroptosis.
肝细胞癌（HCC）是一种既具有毁灭性又常见的疾病。在美国，每年约有24500名男性和10000名女性被诊断为HCC，其中超过一半的确诊患者死于这种疾病。迄今为止，由于各种潜在的合并症，传统疗法对HCC患者并不成功。生存率低和治疗后复发率高表明，正常周围肝脏和HCC的氧化还原环境差异是提高治疗效果的有价值靶点。小白菊内酯（PTL）是一种天然存在的具有抗癌和抗炎特性的治疗药物。PTL可以通过硫醇修饰改变HCC的抗氧化环境，使肿瘤细胞对活性氧（ROS）升高敏感。研究硫醇机制改变与铁介导的脂质过氧化敏感性增加之间的联系，将有助于改善HCC的治疗。用浓度递增的PTL处理的HepG2（人）和McARH7777（大鼠）HCC细胞会降低细胞活力和克隆形成效率。PTL增加了谷胱甘肽（GSH）的氧化，添加GSH前体N-乙酰半胱氨酸（NAC）可使其恢复。此外，硫醇氧化的这种升高导致线粒体功能障碍总体增加。为了阐明细胞死亡是否通过脂质过氧化发生，使用脂质过氧化传感器表明PTL在6小时后增加了脂质氧化水平。此外，蛋白质印迹显示，用PTL处理后谷胱甘肽过氧化物酶4（GPx4）蛋白水平降低，表明细胞在暴露于PTL后无法预防脂质过氧化。脂质过氧化的升高将导致一种称为铁死亡的细胞死亡形式。为了进一步确定铁死亡是HCC关键的死亡机制，在集落存活试验中加入铁抑素-1与PTL联合使用显示出部分恢复。这项研究表明，PTL可通过提高细胞内氧化水平诱导肿瘤细胞死亡，使细胞对铁死亡敏感。
