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Combination Methionine-methylation-axis Blockade: A Novel Approach to Target the Methionine Addiction of Cancer

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

  2. Author Address

    AntiCanc Inc, 7917 Ostrow St, San Diego, CA 92111 USA.Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA.Kanazawa Univ, Dept Orthoped Surg, Kanazawa, Ishikawa, Japan.NCI, Basic Res Lab, Frederick, MD 21701 USA.
    1. Year: 2021
    2. Date: Mar-Apr
  2. Journal: Cancer Genomics Proteomics
  3. Int Inst Anticancer Research
    1. 18
    2. 2
    3. Pages: 113-120
  5. Type of Article: Review
  6. ISSN: 1109-6535
  1. Abstract:

    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/G(2)-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.

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External Sources

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  2. DOI: 10.21873/cgp.20246
  3. PMID: 33608308
  4. PMCID: PMC7943212
  5. View record in Web of Science®
  6. WOS: 000628915300003

Library Notes

  1. Fiscal Year: FY2020-2021
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