Combination methionine-methylation-axis blockade: A novel approach to target the methionine addiction of cancer

Takashi Higuchi, Qinghong Han, Norihiko Sugisawa, Jun Yamamoto, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Kentaro Igarashi, Michael Bouvet, Shree Ram Singh, Hiroyuki Tsuchiya, Robert M. Hoffman

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


Background/Aim: Cancers are selectively sensitive to methionine (MET) restriction (MR) due to their addiction to MET which is overused for elevated methylation reactions. MET addiction of cancer was discovered by us 45 years ago. MR of cancer results in depletion of S-adenosylmethionine (SAM) for transmethylation reactions, resulting in selective cancer-growth arrest in the late S/G2-phase of the cell cycle. The aim of the present study was to determine if blockade of the MET-methylation axis is a highly-effective strategy for cancer chemotherapy. Materials and Methods: In the present study, we demonstrated the efficacy of MET-methylation-axis blockade using MR by oral-recombinant methioninase (o-rMETase) combined with decitabine (DAC), an inhibitor of DNA methylation, and an inhibitor of SAM synthesis, cycloleucine (CL). We determined a proof-of-concept of the efficacy of the MET-methylation-axis blockade on a recalcitrant undifferentiated/unclassified soft-tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) mouse model. Results: The o-rMETase-CL-DAC combination regressed the USTS PDOX with extensive cancer necrosis. Conclusion: The new concept of combination MET-methylation-axis blockade is effective and can now be tested on many types of recalcitrant cancer.

Original languageEnglish
Pages (from-to)113-120
Number of pages8
JournalCancer Genomics and Proteomics
Issue number2
Publication statusPublished - 2021 Apr


  • Cancer
  • Cycloleucine
  • Decitabine
  • MAT2A
  • Methionine addiction
  • Methionine restriction
  • Methionine-methylation-axis blockade
  • PDOX
  • Soft-tissue sarcoma

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cancer Research


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