RT Journal Article
SR Electronic
T1 Combination Methionine-methylation-axis Blockade: A Novel Approach to Target the Methionine Addiction of Cancer
JF Cancer Genomics - Proteomics
JO Cancer Genomics Proteomics
FD International Institute of Anticancer Research
SP 113
OP 120
DO 10.21873/cgp.20246
VO 18
IS 2
A1 HIGUCHI, TAKASHI
A1 HAN, QINGHONG
A1 SUGISAWA, NORIHIKO
A1 YAMAMOTO, JUN
A1 YAMAMOTO, NORIO
A1 HAYASHI, KATSUHIRO
A1 KIMURA, HIROAKI
A1 MIWA, SHINJI
A1 IGARASHI, KENTARO
A1 BOUVET, MICHAEL
A1 SINGH, SHREE RAM
A1 TSUCHIYA, HIROYUKI
A1 HOFFMAN, ROBERT M.
YR 2021
UL http://cgp.iiarjournals.org/content/18/2/113.abstract
AB 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.