PDF(Pubmed)
Abstract：
Ferroptosis is an iron-dependent cell death form that initiates lipid peroxidation (LPO) in tumors. In recent years, there has been growing interest on ferroptosis, but how to propel it forward translational medicine remains in mist. Although experimental ferroptosis inducers such as RSL3 and erastin have demonstrated bioactivity in vitro, the poor antitumor outcome in animal model limits their development. In this study, we reveal a novel ferroptosis inducer, oxaliplatin-artesunate (OART), which exhibits substantial bioactivity in vitro and vivo, and we verify its feasibility in cancer immunotherapy. For mechanism, OART induces cytoplasmic and mitochondrial LPO to promote tumor ferroptosis, via inhibiting glutathione-mediated ferroptosis defense system, enhancing iron-dependent Fenton reaction, and initiating mitochondrial LPO. The destroyed mitochondrial membrane potential, disturbed mitochondrial fusion and fission, as well as downregulation of dihydroorotate dehydrogenase mutually contribute to mitochondrial LPO. Consequently, OART enhances tumor immunogenicity by releasing damage associated molecular patterns and promoting antigen presenting cells maturation, thereby transforming tumor environment from immunosuppressive to immunosensitive. By establishing in vivo model of tumorigenesis and lung metastasis, we verified that OART improves the systematic immune response. In summary, OART has enormous clinical potential for ferroptosis-based cancer therapy in translational medicine.
摘要：
铁凋亡是一种铁依赖性细胞死亡形式，可引发肿瘤中的脂质过氧化（LPO）。近年来,人们对铁中毒的兴趣越来越大，但是如何推动它向前转化医学仍处于迷雾之中。尽管实验性的铁凋亡诱导剂如RSL3和erastin已经在体外证明了生物活性，动物模型中不良的抗肿瘤结果限制了它们的发展。在这项研究中,我们揭示了一种新的铁死亡诱导物，奥沙利铂-青蒿琥酯(OART)，在体外和体内表现出相当大的生物活性，我们验证了其在癌症免疫疗法中的可行性。对于机制，OART诱导细胞质和线粒体LPO促进肿瘤铁性凋亡，通过抑制谷胱甘肽介导的铁凋亡防御系统，增强铁依赖的Fenton反应，启动线粒体LPO。被破坏的线粒体膜电位,受干扰的线粒体融合和裂变，以及二氢乳清酸脱氢酶的下调共同促进线粒体LPO。因此,OART通过释放损伤相关分子模式和促进抗原呈递细胞成熟来增强肿瘤的免疫原性，从而将肿瘤环境从免疫抑制转变为免疫敏感。通过建立体内肿瘤发生和肺转移模型,我们验证了OART改善了系统免疫反应.总之,OART在转化医学中基于铁凋亡的癌症治疗具有巨大的临床潜力。
