Synergy of oral recombinant methioninase (rMETase) and 5-fluorouracil on poorly differentiated gastric cancer.

Abstract

Gastric cancer is highly malignant and recalcitrant to first line chemotherapies that include 5-fluorouracil (5-FU). Cancer cells are addicted to methionine for their proliferation and survival. Methionine addiction of cancer is known as the Hoffman effect. Methionine restriction with recombinant methioninase (rMETase) has been shown to selectively starve cancer cells and has shown synergy with cytotoxic chemotherapy including 5-FU. The present study aimed to investigate the efficacy of rMETase alone and the combination with 5-FU on poorly differentiated human gastric cancer cell lines (MKN45, NUGC3, and NUGC4) in vitro and vivo. rMETase suppressed the tumor growth of 3 kinds of poorly differentiated gastric cancer cells in vitro. The fluorescence ubiquitination-based cell cycle indicator (FUCCI) demonstrated cancer cells treated with rMETase were selectively trapped in the S/G2 phase of the cell cycle. In the present study, subcutaneous MKN45 gastric cancer models were randomized into four groups when the tumor volume reached 100 mm3: G1: untreated control; G2: 5-FU (i.p., 50 mg/kg, weekly, three weeks); G3: oral-rMETase (o-rMETase) (p.o., 100 units/body, daily, three weeks); G4: 5-FU with o-rMETase (5-FU; i.p., 50 mg/kg, weekly, three weeks o-rMETase; p.o., 100 units/body, daily, three weeks). All mice were sacrificed on day 22. Body weight and estimated tumor volume were measured twice a week. 5-FU and o-rMETase suppressed tumor growth as monotherapies on day 18 (p = 0.044 and p = 0.044). However, 5-FU combined with o-rMETase was significantly superior to each monotherapy (p < 0.001 and p < 0.001, respectively) and induced extensive necrosis compared to other groups. The combination of 5-FU and o-rMETase shows promise for transformative therapy for poorly differentiated gastric cancer in the clinic.

• Authors: Masuyo Miyake, Kentaro Miyake, Qinghong Han, Kentaro Igarashi, Kei Kawaguchi, Maryam Barangi, Tasuku Kiyuna, Norihiko Sugisawa, Takashi Higuchi, Hiromichi Oshiro, Zhiying Zhang, Sahar Razmjooei, Michael Bouvet, Itaru Endo, Robert M Hoffman
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 643 Pg. 48-54 (Feb 05 2023) ISSN: 1090-2104 [Electronic] United States
• PMID: 36586158 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Fluorouracil
• L-methionine gamma-lyase
• Carbon-Sulfur Lyases
• Methionine
• Recombinant Proteins

Topics

• Mice
• Humans
• Animals
• Fluorouracil (therapeutic use)
• Stomach Neoplasms (drug therapy)
• Carbon-Sulfur Lyases
• Methionine (metabolism)
• Recombinant Proteins (pharmacology)