1. Combination Methionine-methylation-axis Blockade: A Novel Approach to Target the Methionine Addiction of Cancer
- Author
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Higuchi, Takashi, Han, Qinghong, Sugisawa, Norihiko, Yamamoto, Jun, Yamamoto, Norio, Hayashi, Katsuhiro, Kimura, Hiroaki, Miwa, Shinji, Igarashi, Kentaro, Bouvet, Michael, Singh, Shree Ram, Tsuchiya, Hiroyuki, and Hoffman, Robert M
- Subjects
Brain Disorders ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Animals ,Disease Models ,Animal ,Humans ,Methionine ,Methylation ,Mice ,Mice ,Nude ,Neoplasms ,methionine addiction ,methionine restriction ,methionine-methylation-axis blockade ,decitabine ,cycloleucine ,MAT2A ,soft-tissue sarcoma ,PDOX ,Immunology ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Background/aimCancers 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 methodsIn 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.ResultsThe o-rMETase-CL-DAC combination regressed the USTS PDOX with extensive cancer necrosis.ConclusionThe new concept of combination MET-methylation-axis blockade is effective and can now be tested on many types of recalcitrant cancer.
- Published
- 2021