2. Academic Validation
  3. Ferroptosis-inducing compounds synergize with docetaxel to overcome chemoresistance in docetaxel-resistant non-small cell lung cancer cells

Ferroptosis-inducing compounds synergize with docetaxel to overcome chemoresistance in docetaxel-resistant non-small cell lung cancer cells

  • Eur J Med Chem. 2024 Jul 10:276:116670. doi: 10.1016/j.ejmech.2024.116670.
Wei Huang 1,  Yi Guo 2,  Yazhi Qian 3,  Xiaoang Liu 3,  Gaoxiang Li 4,  Jun Wang 3,  Xiaozhou Yang 3,  Mo Wu 3,  Ying Fan 5,  Haojun Luo 3,  Yuzhu Chen 3,  Liangren Zhang 2,  Nan Yang 3,  Zhenming Liu 6,  Yanyong Liu 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China. Electronic address: huangwei@ibms.pumc.edu.cn.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China.
  • 3 Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China.
  • 4 Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China; Medical College, Tibet University, Lhasa, Tibet Autonomous Region, 850000, PR China.
  • 5 Medical College, Tibet University, Lhasa, Tibet Autonomous Region, 850000, PR China.
  • 6 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, PR China. Electronic address: zmliu@bjmu.edu.cn.
  • 7 Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & School of Basic Medicine, Peking Union Medical College, Beijing, 100005, PR China; Medical College, Tibet University, Lhasa, Tibet Autonomous Region, 850000, PR China. Electronic address: yanyongliu@ibms.pumc.edu.cn.
PMID: 39018922 DOI: 10.1016/j.ejmech.2024.116670
Abstract

Development of resistance to therapy-induced cell death is a major hurdle in the effective treatment of advanced solid tumors. Erastin and RSL3 were originally found to induce synthetic lethality by induction of a novel form of cell death termed Ferroptosis. Emerging evidence suggests that Ferroptosis inducers enhance chemosensitivity of classic therapeutic agents by triggering ferroptotic cell death. In this study we evaluated the effects of erastin and RSL3 on the resistance of docetaxel, doxorubicin, and cisplatin, and revealed a mechanism whereby these Ferroptosis inducers augment docetaxel efficacy in non-small cell lung Cancer by regulating redox signaling to promote Ferroptosis. Transcriptome analysis revealed that combination treatment modulated not only p53 signaling pathway but also immune responses and several signaling pathways including MAPK, NF-κB and PI3K/Akt. Considering that Glutathione Peroxidase 4 (GPX4) serves as the main effector to protect cells from Ferroptosis, this study identified three novel non-covalent GPX4 inhibitors with the aid of pharmacophore-based virtual screening. The new ferroptosis-inducing compounds synergized with docetaxel to increase the cytotoxicity by promoting ferroptotic cell death in docetaxel-resistant A549/DTX cells. Collectively, the induction of Ferroptosis contributed to docetaxel-induced cytotoxic effects and overcame drug resistance in A549/DTX cells. Ferroptosis has a great potential to become a new approach to attenuate resistance to some classic therapeutic drugs in Cancer patients.

Keywords

Chemoresistance; Docetaxel; Ferroptosis; GPX4; Non-small cell lung cancer.

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