2. Academic Validation
  3. Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy

  • J Med Chem. 2023 Aug 24;66(16):11201-11215. doi: 10.1021/acs.jmedchem.3c00659.
Wenjun Wang 1 2,  Foqing Ma 1,  Yuen Tsz Cheung 1,  Guihua Zeng 2,  Yiqin Zhou 1,  Zijing Chen 3,  Lixin Liang 1,  Tuoping Luo 2 3 4,  Rongbiao Tong 1
Affiliations

Affiliations

  • 1 Department of Chemistry, The Hong Kong University of Science and Technology (HKUST), Clear Water Bay, Kowloon, Hong Kong 999077, China.
  • 2 Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518055, China.
  • 3 Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of Education and Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
  • 4 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
PMID: 37578947 DOI: 10.1021/acs.jmedchem.3c00659
Abstract

Induction of Ferroptosis emerges as an effective method for Cancer treatment. With massive efforts to elucidate the Ferroptosis mechanism, the development of new Ferroptosis inducers proceeds rather slowly, with only a few small molecules identified. Herein, we report our discovery of marine alkaloid lepadins E and H as a new class of Ferroptosis inducers. Our in vitro studies show that lepadins E and H exhibit significant cytotoxicity, promote p53 expression, increase ROS production and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate ACSL4 expression, all of which consistently support induction of Ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Our animal model study of lepadin H confirms its in vivo antitumor efficacy with negligible toxicity to normal organs. This work elucidates the mode of action of lepadins (E and H) and verifies their in vivo efficacy as a new class of Ferroptosis inducers for Anticancer therapy with translational potential.

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