2. Academic Validation
  3. Hypoxia-selective prodrug restrains tumor cells through triggering mitophagy and inducing apoptosis

Hypoxia-selective prodrug restrains tumor cells through triggering mitophagy and inducing apoptosis

  • Eur J Med Chem. 2025 Feb 5:283:117155. doi: 10.1016/j.ejmech.2024.117155.
Fangjie Wang 1,  Lairong Song 2,  Qianqian Xu 3,  Ang Jia 4,  Xiangwei Meng 5,  Hongfei Jiang 6,  Renshuai Zhang 7
Affiliations

Affiliations

  • 1 Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou, Henan, 450018, China.
  • 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100071, China.
  • 3 The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China.
  • 4 The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, China.
  • 5 Department of Drug Clinical Trials, Zibo Central Hospital, Zibo, 255036, China. Electronic address: mxwzbszxyy@163.com.
  • 6 The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China. Electronic address: jianghongfei@qdu.edu.cn.
  • 7 The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, 266071, China. Electronic address: zhangrenshuai@qdu.edu.cn.
PMID: 39657461 DOI: 10.1016/j.ejmech.2024.117155
Abstract

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.

Keywords

Antitumor agents; Chalcone derivatives; Hypoxia; Mitophagy; Prodrugs; Safety profile.

Figures
Products