Research ArticleExperimental Studies
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Recombinant Methioninase Increases Eribulin Efficacy 16-fold in Highly Eribulin-resistant HT1080 Fibrosarcoma Cells, Demonstrating Potential to Overcome the Clinical Challenge of Drug-resistant Soft-tissue Sarcoma

SEI MORINAGA, QINGHONG HAN, KOHEI MIZUTA, BYUNG MO KANG, MOTOKAZU SATO, MICHAEL BOUVET, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, HIROYUKI TSUCHIYA, SATORU DEMURA and ROBERT M. HOFFMAN
Anticancer Research September 2024, 44 (9) 3777-3783; DOI: https://doi.org/10.21873/anticanres.17202

Abstract

Background/Aim: A major challenge in treating soft-tissue sarcoma is the development of drug resistance. Eribulin, an anti-tubulin agent, is used as a second-line chemotherapy for patients with unresectable or metastatic soft-tissue sarcoma. However, most patients with advanced soft-tissue sarcoma are resistant to eribulin and do not survive. Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect. The present study aimed to show how much rMETase could increase the efficacy of eribulin on eribulin-resistant fibrosarcoma cells in vitro. Materials and Methods: HT1080 human fibrosarcoma cells were exposed to step-wise increasing concentrations of eribulin from 0.15-0.4 nM to establish eribulin-resistant HT1080 (ER-HT1080). ER-HT1080 cells were cultured in vitro and divided into four groups: untreated control; eribulin treated (0.15 nM); rMETase treated (0.75 U/ml); and eribulin (0.15 nM) plus rMETase (0.75 U/ml) treated. Results: The IC50 of eribulin on ER-HT1080 cells was 0.95 nM compared to the IC50 of 0.15 nM on HT1080 cells, a 6-fold increase. The IC50 of rMETase on ER-HT1080 and HT1080 was 0.87 U/ml and 0.75 U/ml, respectively. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in an inhibition of 80.1% compared to eribulin alone (5.0%) or rMETase alone (47.1%) (p<0.05). rMETase thus increased the efficacy of eribulin 16-fold on eribulin-resistant fibrosarcoma cells. Conclusion: The present study showed that the combination of eribulin and rMETase can overcome high eribulin resistance of fibrosarcoma. The present results demonstrate that combining rMETase with first- or second-line therapy for soft-tissue sarcoma has the potential to overcome the intractable clinical problem of drug-resistant soft-tissue sarcoma.

Key Words:

An intractable clinical problem is drug resistance of soft-tissue sarcoma, which is usually lethal for the patients (1). Eribulin, an anti-tubulin agent is a second-line chemotherapy for patients diagnosed with unresectable or metastatic soft-tissue sarcoma (2). In a clinical trial, 227 patients with advanced soft-tissue sarcoma were given eribulin. Of these patients, 173 patients had progressive disease and 176 patients died (2).

Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect (3, 4). Numerous studies have demonstrated synergy of chemotherapy in combination with methionine restriction effected by rMETase, methionine-free medium, or a methionine-depleted diet (5-44). We have previously showed synergy of rMETase and eribulin on parental HT1080 fibrosarcoma cells in vitro (37).

The present study aimed to show how much rMETase can increase the efficacy of eribulin on highly eribulin-resistant HT1080 fibrosarcoma cells in vitro.

Materials and Methods

Cell culture. The HT1080 cell line was acquired from the American Type Culture Collection (Manassas, VA, USA). The cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) (GIBCO, Grand Island, NY) supplemented with 10% fetal bovine serum (FBS) and 1 IU/ml penicillin/streptomycin.

Reagents. Eribulin was acquired from Eisai Inc. (Nutley, NJ, USA). rMETase was produced by AntiCancer Inc. (San Diego, CA, USA). The procedure for producing rMETase has been previously described (45).

Establishment of eribulin-resistant HT1080 (ER-HT1080). ER-HT1080 cells were established by culturing HT1080 in stepwise increasing concentrations (0.15-0.4 nM) of eribulin for 3 months.

Drug sensitivity assay 1: IC50. Cell viability was determined by utilizing the WST-8 reagent from Dojindo Laboratory (Kumamoto, Japan). The cells (HT1080 or ER-HT1080) were cultivated in 96-well plates with a density of 3,000 cells per well. The culture medium was 100 μl DMEM per well. The cells were then incubated at 37°C overnight. HT1080 or ER-HT1080 cells were exposed to escalating concentrations of eribulin, ranging from 0.5 nM to 8 nM, for 72 h. HT1080 cells or ER-HT1080 cells were treated with increasing concentrations of rMETase, ranging from 0.5 U/ml to 8 U/ml, for 72 h. After the culture period, 10 μl of a WST-8 solution was added to each well, and the plate was further incubated for 1 h at 37°C. A microplate reader (SUNRISE: TECAN, Mannedorf, Switzerland) was used to measure absorption at 450 nm. Drug sensitivity curves were generated using Microsoft Excel for Mac 2016 ver. 15.52 (Microsoft, Redmond, WA, USA). The half-maximal inhibitory concentration (IC50) values were calculated using ImageJ ver. 1.53k (National Institutes of Health, Bethesda, MD, USA). The experiments were conducted in triplicate, with each experiment being repeated twice. Viability of HT1080 cells after eribulin and rMETase treatment was determined as previously described (37).

Drug sensitivity assay 2: Synergy. ER-HT1080 cells were seeded at 3,000 cells/well in 96-well plates. Twenty-four hours later, four treatment groups were established [control (DMEM); eribulin (0.15 nM); rMETase (0.75 U/ml); eribulin (0.15 nM) plus rMETase (0.75 U/ml)]. Seventy-two hours later, cell viability was measured in triplicate as described above. In the present study, we defined synergy as an effective combination greater than either component alone.

Statistical analyses were performed using EZR software developed by the Saitama Medical Center, Jichi Medical University, Saitama, Japan (46). Tukey-Kramer analysis was conducted to examine the relationships between variables. Statistically significant results were defined as those with p-values ≤ 0.05.

Results

Drug sensitivity assay 1: IC50 of eribulin and rMETase on HT1080 and ER-HT1080 cells. The IC50 value of eribulin on HT1080 cells was 0.15 nM [data from (37)]. The IC50 of eribulin on ER-HT1080 cells was 0.95 nM, a six-fold increase in resistance. The IC50 for rMETase on HT1080 cells was 0.75 U/ml [data from (37)] and the IC50 of rMETase on ER-HT1080 cells was 0.87 U/ml, demonstrating that the efficacy of rMETase alone on ER-HT1080 cells was similar to that on HT1080 cells (Figure 1).

Figure 1.
Figure 1.

IC50 of eribulin and rMETase on HT1080 and ER-HT1080 cells (mean±SD, n=3). A) IC50 of eribulin on HT1080 cells [data from (37)]. B) IC50 of eribulin on ER-HT1080 cells. C) IC50 of r-METase on HT1080 cells [data from (37)]. D) IC50 of r-METase on ER-HT1080 cells. rMETase: recombinant methioninase; ER-HT1080: eribulin-resistant HT1080.

Drug sensitivity assay 2: Synergy of rMETase and eribulin on ER-HT1080 cells. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in lethality of 80.1% of the cells compared to eribulin alone (5.0%), or rMETase alone (47.1%) (p<0.05) (Figure 2). rMETase increased the efficacy of eribulin on ER-HT1080 cells 16-fold.

Figure 2.
Figure 2.

Synergy of the combination of eribulin and rMETase on ER-HT1080 cells. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in 80.1% lethality of the cells compared to eribulin alone (5.0%) and rMETase alone (47.1%).

Discussion

An intractable clinical problem in treating soft-tissue sarcoma is drug resistance. Once drug resistance is established, therapeutic options for soft-tissue sarcoma are severely restricted due to the lack of effective drugs for the disease (47). Next-generation therapy is urgently needed.

ER-HT1080 cells were 6-fold-more resistant to eribulin than HT1080 cells. However, ER-HT1080 cells were as sensitive to rMETase as HT1080 cells. The combination of eribulin (0.15 nM) and rMETase (0.75 U/ml) (which were the IC50s for HT1080) on ER-HT1080 cells resulted in a 16-fold increase in the efficacy of eribulin. The present results have future clinical potential to solve the intractable clinical problem of drug-resistant soft-tissue sarcoma.

rMETase is effective since it targets the fundamental and universal hallmark of cancer, methionine addiction, and is showing clinical promise (3, 15, 22, 39, 48-78).

Acknowledgements

This article is dedicated to the memory of A.R. Moossa, MD, Sun Lee, MD, Professor Gordon H. Sato, Professor Li Jiaxi, Masaki Kitajima, MD, Joseph R. Bertino, MD, Shigeo Yagi, PhD, J.A.R Mead, Ph.D., Eugene P. Frenkel, MD, Professor Lev Bergelson, Professor Sheldon Penman, Professor John R. Raper, and Joseph Leighton, MD. The Robert M. Hoffman Foundation for Cancer Research provided funds for the present study.

Footnotes

  • Authors’ Contributions

    SM and RMH designed the study. QH provided rMETase. SM performed experiments. SM was the major contributor to writing the article and RMH revised the article. KM, BMK, MS, MB, NY, KH, HK, SM, KI, TH, HT and SD critically read the manuscript.

  • Conflicts of Interest

    The Authors declare that there are no competing interests in relation to this study.

  • Received June 22, 2024.
  • Revision received July 15, 2024.
  • Accepted July 16, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Recombinant Methioninase Increases Eribulin Efficacy 16-fold in Highly Eribulin-resistant HT1080 Fibrosarcoma Cells, Demonstrating Potential to Overcome the Clinical Challenge of Drug-resistant Soft-tissue Sarcoma
SEI MORINAGA, QINGHONG HAN, KOHEI MIZUTA, BYUNG MO KANG, MOTOKAZU SATO, MICHAEL BOUVET, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, HIROYUKI TSUCHIYA, SATORU DEMURA, ROBERT M. HOFFMAN
Anticancer Research Sep 2024, 44 (9) 3777-3783; DOI: 10.21873/anticanres.17202
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