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

doi:10.21873/CGP.20246

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

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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/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 language	English
Pages (from-to)	113-120
Number of pages	8
Journal	Cancer Genomics and Proteomics
Volume	18
Issue number	2
DOIs	https://doi.org/10.21873/CGP.20246
Publication status	Published - 2021 Apr

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.21873/CGP.20246

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Higuchi, T., Han, Q., Sugisawa, N., Yamamoto, J., Yamamoto, N., Hayashi, K., Kimura, H., Miwa, S., Igarashi, K., Bouvet, M., Singh, S. R., Tsuchiya, H., & Hoffman, R. M. (2021). Combination methionine-methylation-axis blockade: A novel approach to target the methionine addiction of cancer. Cancer Genomics and Proteomics, 18(2), 113-120. https://doi.org/10.21873/CGP.20246

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

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/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.",

keywords = "Cancer, Cycloleucine, Decitabine, MAT2A, Methionine addiction, Methionine restriction, Methionine-methylation-axis blockade, PDOX, Soft-tissue sarcoma",

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

year = "2021",

month = apr,

doi = "10.21873/CGP.20246",

language = "English",

volume = "18",

pages = "113--120",

journal = "Cancer Genomics and Proteomics",

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T1 - Combination methionine-methylation-axis blockade

T2 - A novel approach to target the methionine addiction of cancer

AU - Higuchi, Takashi

AU - Han, Qinghong

AU - Sugisawa, Norihiko

AU - Yamamoto, Jun

AU - Yamamoto, Norio

AU - Hayashi, Katsuhiro

AU - Kimura, Hiroaki

AU - Miwa, Shinji

AU - Igarashi, Kentaro

AU - Bouvet, Michael

AU - Singh, Shree Ram

AU - Tsuchiya, Hiroyuki

AU - Hoffman, Robert M.

PY - 2021/4

Y1 - 2021/4

N2 - 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.

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.

KW - Cancer

KW - Cycloleucine

KW - Decitabine

KW - MAT2A

KW - Methionine addiction

KW - Methionine restriction

KW - Methionine-methylation-axis blockade

KW - PDOX

KW - Soft-tissue sarcoma

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SN - 1109-6535

VL - 18

SP - 113

EP - 120

JO - Cancer Genomics and Proteomics

JF - Cancer Genomics and Proteomics

IS - 2

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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