Triple-Methyl Blockade with Recombinant Methioninase, Cycloleucine, and Azacitidine Arrests a Pancreatic Cancer Patient-Derived Orthotopic Xenograft Model

Norihiko Sugisawa, Jun Yamamoto, Qinghong Han, Yuying Tan, Yoshihiko Tashiro, Hiroto Nishino, Sachiko Inubushi, Kazuyuki Hamada, Kei Kawaguchi, Michiaki Unno, Michael Bouvet, Robert M. Hoffman

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Objectives Methionine addiction is a fundamental and general hallmark of cancer caused by enhanced methyl flux. In the present study, we effected a novel methionine-methylation blockade to target a patient-derived orthotopic xenograft model of pancreatic cancer. Methods The pancreatic cancer patient-derived orthotopic xenograft mouse models were randomized into 6 groups of 8 mice each and treated for 2 weeks: untreated control; azacitidine; oral recombinant methioninase (o-rMETase); o-rMETase plus cycloleucine; o-rMETase plus cycloleucine plus azacitidine (triple-methyl blockade therapy); and gemcitabine (positive control). Results Triple-methyl blockade therapy arrested tumor growth (mean relative tumor volume, 1.03 [standard deviation, 0.36]) and was significantly more effective compared with azacitidine (P = 0.0001); o-rMETase (P = 0.007); or o-rMETase plus cycloleucine (P = 0.04). Gemcitabine alone also inhibited but did not arrest tumor growth (mean relative tumor volume, 1.50 [standard deviation, 0.30]). The percentage of cancer cells that were negative for 5-methylcytosine staining in immunohistochemistry, indicating reduction of DNA methylation, increased with triple-methyl blockade therapy (37.5%), compared with gemcitabine (1.8%); o-rMETase (2.8%); azacitidine (9.0%); or o-rMETase plus cycloleucine (10.6%). Conclusions This new concept of triple-methyl blockade therapy has clinical potential for pancreatic cancer, which is currently a recalcitrant disease.

Original languageEnglish
Pages (from-to)93-98
Number of pages6
JournalPancreas
Volume50
Issue number1
DOIs
Publication statusPublished - 2021

Keywords

  • DNA methylation
  • S-Adenosylmethionine
  • azacitidine
  • cycloleucine
  • pancreatic cancer
  • recombinant methioninase

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Endocrinology

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