Homoharringtonine as a PHGDH inhibitor: Unraveling metabolic dependencies and developing a potent therapeutic strategy for high-risk neuroblastoma

Chiao Hui Hsieh, Chen Tsung Huang, Yi Sheng Cheng, Chun Hua Hsu, Wen Ming Hsu, Yun Hsien Chung, Yen Lin Liu, Tsai Shan Yang, Chia Yu Chien, Yu Hsuan Lee, Hsuan Cheng Huang*, Hsueh Fen Juan*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Neuroblastoma, a childhood cancer affecting the sympathetic nervous system, continues to challenge the development of potent treatments due to the limited availability of druggable targets for this aggressive illness. Recent investigations have uncovered that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme for de novo serine synthesis, serves as a non-oncogene dependency in high-risk neuroblastoma. In this study, we show that homoharringtonine (HHT) acts as a PHGDH inhibitor, inducing intricate alterations in cellular metabolism, and thus providing an efficient treatment for neuroblastoma. We have experimentally verified the reliance of neuroblastoma on PHGDH and employed molecular docking, thermodynamic evaluations, and X-ray crystallography techniques to determine the bond interactions between HHT and PHGDH. Administering HHT to treat neuroblastoma resulted in effective cell elimination in vitro and tumor reduction in vivo. Metabolite and functional assessments additionally disclosed that HHT treatment suppressed de novo serine synthesis, initiating intricate metabolic reconfiguration and oxidative stress in neuroblastoma. Collectively, these discoveries highlight the potential of targeting PHGDH using HHT as a potent approach for managing high-risk neuroblastoma.

Original languageEnglish
Article number115429
JournalBiomedicine and Pharmacotherapy
Volume166
DOIs
StatePublished - Oct 2023

Keywords

  • Computational molecular docking
  • Drug discovery
  • High-risk neuroblastoma
  • Metabolic reprogramming
  • Molecular target therapy
  • Phosphoglycerate dehydrogenase

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