Wang Fangjie, Song Lairong, Xu Qianqian, Jia Ang, Meng Xiangwei, Jiang Hongfei, Zhang Renshuai
Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou, Henan, 450018, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100071, China.
Eur J Med Chem. 2025 Feb 5;283:117155. doi: 10.1016/j.ejmech.2024.117155. Epub 2024 Dec 7.
Hypoxia is a common feature of various solid tumors, which reduces the sensitivity of tumor cells to both radiotherapy and chemotherapy. However, hypoxia also presents an opportunity for tumor-selective therapy. The prodrug strategy, leveraging the hypoxic nature of the tumor microenvironment, shows significant potential for clinical application. Here we present CHD-1, a hypoxia-activated antitumor prodrug that activates in hypoxic environments, effectively inhibiting hypoxic tumor cells while exhibiting no toxicity to normoxic cells. CHD-1 impairs mitochondrial morphology and membrane potential of hypoxic tumor cells, further triggers excessive mitophagy and induces apoptosis. Moreover, prodrug CHD-1 significantly inhibits HeLa xenograft growth in vivo, and shows lower toxicity than parent molecule in an acute toxicity assessment in animal models. This study introduces a promising hypoxia-activated antitumor prodrug with strong potential for further development in hypoxic tumor therapy.
缺氧是各种实体瘤的一个常见特征，它会降低肿瘤细胞对放疗和化疗的敏感性。然而，缺氧也为肿瘤选择性治疗提供了契机。利用肿瘤微环境缺氧特性的前药策略在临床应用中显示出巨大潜力。在此，我们展示了CHD-1，一种在缺氧环境中激活的缺氧激活抗肿瘤前药，它能有效抑制缺氧肿瘤细胞，同时对正常氧合细胞无毒。CHD-1破坏缺氧肿瘤细胞的线粒体形态和膜电位，进一步引发过度的线粒体自噬并诱导凋亡。此外，前药CHD-1在体内显著抑制HeLa异种移植瘤的生长，并且在动物模型的急性毒性评估中显示出比母体分子更低的毒性。本研究引入了一种有前景的缺氧激活抗肿瘤前药，在缺氧肿瘤治疗中具有进一步开发的强大潜力。
