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

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 r...

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Published inCancer genomics & proteomics Vol. 18; no. 2; pp. 113 - 120
Main Authors 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, Hoffman, Robert M
Format Journal Article
LanguageEnglish
Published Greece International Institute of Anticancer Research 01.03.2021
Subjects
5-aza-2'-deoxycytidine
Addictions
Adenosylmethionine
Cancer
Cell cycle
Chemotherapy
Depletion
DNA methylation
Inhibitors
Methionine
Necrosis
S-Adenosylmethionine
Sarcoma
Xenografts
Xenotransplantation
methionine-methylation-axis blockade
MAT2A
cycloleucine
soft-tissue sarcoma
methionine addiction
methionine restriction
PDOX
decitabine
Cancer
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Summary: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 -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. 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. The o-rMETase-CL-DAC combination regressed the USTS PDOX with extensive cancer necrosis. The new concept of combination MET-methylation-axis blockade is effective and can now be tested on many types of recalcitrant cancer.
ISSN:1109-6535
1790-6245
DOI:10.21873/cgp.20246