Research ArticleExperimental Studies
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DNA-Binding Agent Trabectedin Combined With Recombinant Methioninase Is Synergistic to Decrease Fibrosarcoma Cell Viability and Induce Nuclear Fragmentation But Not Synergistic on Normal Fibroblasts

SEI MORINAGA, QINGHONG HAN, YUTARO KUBOTA, 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 June 2024, 44 (6) 2359-2367; DOI: https://doi.org/10.21873/anticanres.17043

Abstract

Background/Aim: The alkylating agent trabectedin, which binds the minor groove of DNA, is second-line therapy for soft-tissue sarcoma but has only moderate efficacy. The aim of the present study was to determine the synergistic efficacy of recombinant methioninase (rMETase) and trabectedin on fibrosarcoma cells in vitro, compared with normal fibroblasts. Materials and Methods: HT1080 human fibrosarcoma cells expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in the cytoplasm and Hs27 normal human fibroblasts, were used. Each cell line was cultured in vitro and divided into four groups: no-treatment control; trabectedin treated; rMETase treated; and trabectedin plus rMETase treated. The dual-color HT1080 cells were used to quantitate nuclear fragmentation in each treatment group. Results: The combination of rMETase and trabectedin was highly synergistic to decrease HT1080 cell viability. In contrast, there was no synergy on Hs27 cells. Moreover, nuclear fragmentation occurred synergistically with the combination of trabectedin and rMETase on dual-color HT1080 cells. Conclusion: The combination treatment of trabectedin plus rMETase was highly synergistic on fibrosarcoma cells in vitro suggesting that the combination can improve the outcome of trabectedin alone in future clinical studies. The lack of synergy of rMETase and trabectedin on normal fibroblasts suggests the combination is not toxic to normal cells. Synergy of the two drugs may be due to the high rate of nuclear fragmentation on treated HT1080 cells, and the late-S/G2 cell-cycle block of cancer cells by rMETase, which is a target for trabectedin. The results of the present study suggest the future clinical potential of the combination of rMETase and trabectedin for soft-tissue sarcoma.

Key Words:

Soft tissue sarcoma is a heterogeneous but rare disease accounting for only 1% to 2% of all cancer cases (1). Currently, the World Health Organization (WHO) has classified this diverse group of cancers into over 100 histological subtypes (2).

Trabectedin is an alkylating agent that binds covalently to DNA’s minor groove, impairing transcription and arrests the cell cycle in the late S/G2 phase, which triggers apoptosis (3). Trabectedin has been used as a second-line treatment for patients with soft-tissue sarcomas following the failure of first-line treatment with doxorubicin and ifosfamide (3).

Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect (4-6). Numerous studies have shown the synergistic efficacy of rMETase or methionine-free medium or a methionine-depleted diet, and chemotherapy (7-40). The synergy between trabectedin and rMETase has not been described.

The present study sought to determine the synergistic efficacy between rMETase and trabectedin on fibrosarcoma cells in vitro compared to normal fibroblasts.

Materials and Methods

Cell culture. Hs27 normal fibroblasts were acquired from the American Type Culture Collection (Manassas, VA, USA). HT1080 expressing red fluorescent protein (RFP) in the cytoplasm and green fluorescent protein (GFP) in the nucleus were previously established at AntiCancer Inc. (San Diego, CA, USA). Dulbecco’s modified Eagle’s medium (DMEM) (GIBCO, Grand Island, NY, USA), supplemented with 10% fetal bovine serum (FBS) and 1 IU/ml of penicillin/streptomycin, was used to cultivate the cells.

Regents. Trabectedin was obtained from PharmaMar (Horsham, PA, USA). Recombinant methioninase (rMETase) was produced in AntiCancer Inc. The rMETase production process was as previously described (41).

Drug sensitivity assay 1: IC50. Utilizing the WST-8 reagent (Dojindo Laboratory, Kumamoto, Japan), cell viability was measured. HT1080 and Hs27 were cultivated in 96-well plates with 3,000 cells per well in DMEM (100 μl/well) and incubated overnight at 37°C. Cells were exposed to varying concentrations of either rMETase (0.5 U/ml to 8 U/ml) or trabectedin (1 nM to 40 nM) for 72 h. The WST-8 solution (10 μl) was added to each well at the conclusion of the culture period, and the plate was then further incubated for 1 hour at 37°C. A microplate reader (SUNRISE: TECAN, Mannedorf, Switzerland) was used to measure the absorption at 450 nm. Microsoft Excel for Mac 2016 version 15.52 (Microsoft, Redmond, WA, USA) was used to create drug sensitivity curves, and ImageJ version 1.53k (National Institutes of Health, Bethesda, MD, USA) was used to determine half-maximal inhibitory concentrations (IC50) values. Each experiment was run three times in triplicate.

Drug sensitivity assay 2: Synergy. HT1080 and Hs27 were seeded at 3,000 cells per well in 96-well plates. Four treatments were performed twenty-four hours later on each cell line: 1) Control (DMEM); 2) trabectedin, IC50; 3) rMETase, IC50; and 4) trabectedin, IC50 plus rMETase, IC50. Cell viability was assessed 72 h later as described above.

Nuclear fragmentation assay. Dual-color HT1080 cells, which had GFP in the nucleus and RFP in the cytoplasm, were used as previously described to visualize nuclear and cytoplasmic dynamics (40-47). Dual-color cells were examined under an Olympus IX71 microscope (×200) (Olympus corp., Tokyo, Japan). Cells (300,000) per well were seeded in 6-well plates. All treatment groups were divided into the following groups 1) Control (DMEM); 2) trabectedin (3.3 nM); 3) rMETase (0.75 U/ml); 4) trabectedin (3.3 nM) plus rMETase (0.75 U/ml). Six measurements were made of the number of fragmented nuclei per field of view, 48 h after the start of treatment.

Statistical analysis. EZR software (Saitama Medical Center, Jichi Medical University, Saitama, Japan) was used for all statistical analyses. The Tukey-Kramer analysis was used to test associations between variables. p-Values ≤0.05 were deemed statistically significant.

Results

Drug sensitivity assay 1: IC50 of trabectedin and rMETase on HT1080 and Hs27 cells. The IC50 value of HT 1080 for trabectedin was 3.3 nM. The IC50 of trabectedin on Hs27 was 6.34 nM. The IC50 for rMETase on HT1080 was 0.75 U/ml (data from [40]). The IC50 of rMETase on Hs27 was 0.93 U/ml (data from [40]) (Figure 1).

Figure 1.
Figure 1.

Trabectedin and rMETase treatment of HT1080 and Hs27 cells (mean±SD, n=3). (A) Sensitivity to trabectedin of HT1080. (B) Sensitivity to rMETase of HT1080 (data from [40]). (C): Sensitivity to trabectedin of Hs27. (D): Sensitivity to rMETase of Hs27 (data from [40]).

Drug sensitivity assay 2: Synergy. Trabectedin (3.3 nM) plus rMETase (0.75 U/ml) was synergistic to decrease HT1080 cell viability (p<0.05). In contrast, trabectedin (6.34 nM) plus rMETase (0.93 U/ml) did not show synergy for Hs27 cells (Figure 2A and B).

Figure 2.
Figure 2.

Efficacy of combination of trabectedin and rMETase on fibrosarcoma and normal fibroblasts. (A) HT1080 fibrosarcoma cells. Control (DMEM); trabectedin (3.3 nM); rMETase (0.75 U/ml); trabectedin (3.3 nM) plus rMETase (0.75 U/ml). (B) Hs27 fibroblasts. Control (DMEM); trabectedin (6.34 nM); rMETase (0.93 U/ml); trabectedin (6.34 nM) plus rMETase (0.93 U/ml). n=3, *p<0.05.

Nuclear fragmentation assay. Trabectedin (3.3 nM) plus rMETase (0.75 U/ml) was synergistic to fragment nuclei of HT1080 cells (p<0.05) (Figure 3A-C).

Figure 3.
Figure 3.

Efficacy of trabectedin, rMETase and their combination on nuclear fragmentation in HT 1080 cells which express RFP in the cytoplasm and GFP in the nucleus. (A, B) Images of nuclei expressing GFP. Control (DMEM); trabectedin (3.3 nM); rMETase (0.75 U/ml); trabectedin (3.3nM) plus rMETase (0.75 U/ml). Scale bars: 100 μm. (C) Nuclear fragmentation quantitation. Control (DMEM); trabectedin (3.3 nM); rMETase (0.75 U/ml); trabectedin (3.3 nM) plus rMETase (0.75 U/ml) (p<0.05 compared to all other groups).

Discussion

Patients with soft tissue sarcomas are treated with trabectedin as second-line treatment after first-line anthracycline-based chemotherapy fails (48). The 6-month progression-free survival rates of patients with metastatic and unresectable soft tissue sarcoma who were treated with trabectedin were 35-40% (49-53).

Methionine addiction of cancer was discovered by one of us (RMH) in 1976 (4). Methionine addiction is a general and fundamental hallmark of cancer (4-6, 54-56). The combination of rMETase and chemotherapy is synergistic for many drugs (7-40). The synergy between rMETase and trabectedin on HT1080 cells in the present study may be due to both rMETase and trabectedin causing S/G2 cell-cycle trapping (57, 58). For Hs27 cells, however, trabectedin plus rMETase did not exhibit synergy since normal cells do not arrest in the S/G2 phase of the cell cycle when restricted of methionine. We have previously shown that the combination of rMETase and eribulin is synergistic on HT1080 cells but not Hs27, for similar reasons (40).

Previous studies have shown that trabectedin efficacy for cancer was dependent on the status of both nucleotide excision repair and homologous recombination DNA repair pathways (59-63). In the present study, trabectedin combined with rMETase was synergistic for nuclear fragmentation. Nuclear fragmentation synergy may be due to the cell-cycle arrest in S/G2 by both agents.

In conclusion, the combination treatment of trabectedin plus rMETase was highly synergistic on fibrosarcoma cells in vitro suggesting that the combination can improve the outcome of trabectedin alone in future clinical studies. The lack of synergy of rMETase and trabectedin on normal fibroblasts suggests the combination is not toxic to normal cells. Synergy of the two drugs results in a high rate of nuclear fragmentation in HT1080 cells. The results of the present study suggest the future clinical potential of the combination of rMETase and trabectedin for soft-tissue sarcoma. The combination of rMETase and trabectedin is effective since rMETase targets the fundamental hallmark of cancer, methionine addiction (4-6, 54-56, 64-84), known as the Hoffman effect (4-6, 85-87). rMETase arrests cancer cells in late S/G2 where trabectedin is most active (57, 58). Synergy of rMETase and chemotherapy appears to be a general hallmark of cancer (7-40, 88-92), including in the clinic (17, 24, 93-97).

Acknowledgements

This paper is dedicatd to the memory of A.R. Moosa, MD, Sun Lee, MD, Professor Gordon H. Sato, Professor Li Jiaxi, Masaki Kitajima, MD, Shigeo Yagi, PhD, Jack Geller, MD, Joseph R Bertino, MD, J.A.R. Mead, PhD, Eugene P. Frenkel, MD, Professor Lev Bergelson, Professor Sheldon Penman, Professor John R. Raper and Joseph Leighton, MD.

Footnotes

  • Authors’ Contributions

    SM, HQ, YK, KM, BMK, MS, MB, NY, KH, HK, SM, KI, TH, HT, SD and RMH designed the study. SM performed experiments. SM was a major contributor to writing the manuscript and RMH revised the paper. All Authors read and approved the final manuscript.

  • Conflicts of Interest

    The Authors declared that there are no competing interests.

  • Funding

    The Robert M. Hoffman Foundation for cancer research supported the present study.

  • Received March 12, 2024.
  • Revision received April 19, 2024.
  • Accepted May 2, 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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DNA-Binding Agent Trabectedin Combined With Recombinant Methioninase Is Synergistic to Decrease Fibrosarcoma Cell Viability and Induce Nuclear Fragmentation But Not Synergistic on Normal Fibroblasts
SEI MORINAGA, QINGHONG HAN, YUTARO KUBOTA, 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 Jun 2024, 44 (6) 2359-2367; DOI: 10.21873/anticanres.17043
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