Research ArticleExperimental Studies
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Recombinant Methioninase Is Selectively Synergistic With Doxorubicin Against Wild-type Fibrosarcoma Cells Compared to Normal Cells and Overcomes Highly-Doxorubicin-resistant Fibrosarcoma

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 August 2024, 44 (8) 3261-3268; DOI: https://doi.org/10.21873/anticanres.17144

Abstract

Background/Aim: Doxorubicin is first-line therapy for soft-tissue sarcoma, but patients can develop resistance which is usually fatal. As a novel therapeutic strategy, the present study aimed to determine the synergy of recombinant methioninase (rMETase) and doxorubicin against HT1080 fibrosarcoma cells compared to Hs27 normal fibroblasts, and rMETase efficacy against doxorubicin-resistant HT1080 cells in vitro. Materials and Methods: The 50% inhibitory concentrations (IC50) of doxorubicin and rMETase, as well as their combination efficacy, against HT1080 human fibrosarcoma cells, Hs27 normal human fibroblasts and doxorubicin-resistant HT1080 (DR-HT1080) cells were determined. Dual-color HT1080 cells which expressed red fluorescent protein (RFP) in the cytoplasm and green fluorescent protein (GFP) in the nuclei were used to visualize nuclear fragmentation during treatment. Nuclear fragmentation was observed with an IX71 fluorescence microscope. Results: The IC50 for doxorubicin was 3.3 μM for HT1080 cells, 12.4 μM for DR-HT1080 cells, and 7.25 μM for Hs27 cells. The IC50 for rMETase was 0.75 U/ml for HT1080 cells, 0.42 U/ml for DR-HT1080 cells, and 0.93 U/ml for Hs27 cells. The combination of rMETase and doxorubicin was synergistic against fibrosarcoma cells but not against normal fibroblasts. The combination of doxorubicin plus rMETase also caused more fragmented nuclei than either treatment alone in HT1080 cells. rMETase alone was highly effective against the DR-HT1080 cells as well as the parental HT1080 cells. Conclusion: The present results indicate the future clinical potential of rMETase in combination with doxorubicin for fibrosarcoma, including doxorubicin-resistant fibrosarcoma.

Key Words:

Fibrosarcoma is a recalcitrant disease (1). Doxorubicin is first-line treatment for fibrosarcoma, but patients can develop doxorubicin resistance which is usually fatal (2).

Multiple studies have shown that the combination of recombinant methioninase (rMETase) and chemotherapy is synergistic against cancer cells in vitro, in mouse models and in the clinic, as it targets methionine addiction, a general and fundamental hallmark of cancer, known as the Hoffman effect (3-33).

The objective of the present study was to determine the synergy of rMETase and doxorubicin on fibrosarcoma cells, compared to normal fibroblasts, and to determine rMETase efficacy on highly-doxorubicin-resistant fibrosarcoma cells in vitro.

Materials and Methods

Cells. The HT1080 human fibrosarcoma cell line and Hs27 normal human fibroblasts were acquired from the American Type Culture Collection (Manassas, VA, USA). The cells were cultivated in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum and 1 IU/ml penicillin/streptomycin. HT1080 cells were previously transfected with DsRed-2 red fluorescent protein (RFP), expressed in the cytoplasm, and histone H2B green fluorescent protein (GFP), expressed in the nucleus (34-39).

Regents. Doxorubicin was obtained from Bedford Laboratories (Bedford, OH, USA). rMETase was produced by AntiCancer Inc. (San Diego, CA, USA) as previously described (40).

Generation of doxorubicin-resistant HT1080 (DR-HT1080) cells. To generate DR-HT1080 cells, HT1080 cells were cultured for 3 months in step-wise increasing concentrations of doxorubicin (8 nM-6.4 μM).

Determination of half-maximal inhibitory concentrations (IC50) of rMETase and doxorubicin. Cell viability was assessed using the WST-8 reagent (Dojindo Laboratory, Kumamoto, Japan). Cells (HT1080, DR-HT1080 and Hs27) were cultured in 96-well plates (3,000 cells/well) in Dulbecco’s Modified Eagle’s Medium (DMEM) (GIBCO, Grand Island, NY, USA) (100 μl/well) and incubated at 37°C overnight. The cells were subjected to increasing concentrations of doxorubicin, ranging from 1 μM to 40 μM, or rMETase, ranging from 0.5 U/ml to 8 U/ml, for 72 h to determine the 50% inhibitory concentration (IC50). After the culture period, 10 μl of the WST-8 solution was added to each well. The plates were then incubated for an additional hour at 37°C. Absorption at 450 nm was recorded with a microplate reader (Sunrise; Tecan, Mannedorf, Switzerland). Drug-sensitivity curves were generated using Microsoft Excel for Mac 2016 ver. 15.52 (Microsoft, Redmond, WA, USA), and the IC50 values were determined using ImageJ ver. 1.53k (National Institutes of Health, Bethesda, MD, USA). Experiments were conducted twice, each in triplicate.

Determination of synergy of rMETase and doxorubicin. HT1080 or Hs27 cells were seeded at a density of 3,000 cells per well in 96-well plates. After 24 h, four different types of treatments were carried out: control (DMEM only), doxorubicin (at IC50), rMETase (at IC50), and a combination of doxorubicin with rMETase (at the IC50 of each). After 72 h, the viability of the cells was assessed as described above. In the present study, we defined synergy as sensitivity to a combination of agents with greater efficacy than to either agent alone.

Nuclear fragmentation assay. Dual-color HT1080 cells expressing RFP in the cytoplasm and GFP in the nucleus (34-39) were used to determine nuclear fragmentation of HT1080 cells treated with rMETase, doxorubicin, and their combination. The cells were seeded at a density of 300,000 cells per well in 6-well plates. Treatments were: control (DMEM), doxorubicin (3.3 μM alone), rMETase (0.75 U/ml) alone, or doxorubicin (3.3 μM) plus rMETase (0.75 U/ml). After 48 h, the cells were examined using an IX71 fluorescence microscope (Olympus, Tokyo, Japan) at a magnification of ×200. The number of fragmentated nuclei was quantified per visual field on six separate fields.

Statistical analysis. Statistical analysis was performed using EZR software, developed by the Saitama Medical Center and Jichi Medical University in Saitama, Japan (41). A Tukey–Kramer analysis was employed to examine the relationships between variables. Statistically-significant results were defined as those with p-values less than 0.05.

Results

Determination of the IC50 of doxorubicin and rMETase against HT1080, DR-HT1080 and Hs27 cells. The IC50 of doxorubicin against HT1080 cells was 3.3 μM, and was 12.4 μM against DR-HT 1080 cells. The IC50 of rMETase against HT1080 cells was 0.75 U/ml [data from (42)] and was 0.42 U/ml against DR-HT1080 cells. The IC50 of doxorubicin against Hs27 normal fibroblasts was 7.25 μM and that of rMETase was 0.93 U/ml [data from (42)] (Figure 1).

Figure 1.
Figure 1.

Doxorubicin and recombinant methioninase (rMETase) sensitivity of HT1080 fibrosarcoma cells, doxorubicin-resistant HT1080 fibrosarcoma cells (DR-HT1080) and Hs27 normal fibroblasts (mean±standard deviation), n=3. (A) Sensitivity of HT1080 and DR-HT1080 cells to doxorubicin. (B) Sensitivity of HT1080 and DR-HT1080 cells to rMETase. (C) Sensitivity of Hs27 cells to doxorubicin and rMETase.

Synergy of rMETase and doxorubicin on the viability of HT1080 fibrosarcoma cells but not Hs27 normal fibroblasts. The combination of doxorubicin (3.3 μM) plus rMETase (0.75 U/ml) was synergistic on reducing the viability of HT1080 cells (p<0.05). In contrast, doxorubicin (7.25 μM) plus rMETase (0.93 U/ml) did not show synergy on reducing the viability of Hs27 cells (Figure 2).

Figure 2.
Figure 2.

Synergy of the combination of doxorubicin and recombinant methioninase (rMETase) on HT1080 fibrosarcoma cells (A) and not on Hs27 normal fibroblasts (B). Control: Dulbecco’s modified Eagle’s medium. Doxorubicin IC50: 3.3 μM on HT1080 and 7.25 μM on Hs27; rMETase IC50: 0.75 U/ml on HT1080 and 0.93 U/ml on Hs27 [data from (42)]; combination treatments used the same concentrations as in single treatments. *Significantly different at p<0.05 (n=3).

Synergy of rMETase and doxorubicin on nuclear fragmentation of HT1080 cells. The combination of doxorubicin (3.3 μM) plus rMETase (0.75 U/ml) caused significantly more fragmentated nuclei in HT1080 cells than doxorubicin alone or rMETase alone (p<0.05) (Figure 3).

Figure 3.
Figure 3.

Effect of doxorubicin alone, recombinant methioninase (rMETase) alone and their combination on nuclear fragmentation in HT1080 cells. Cells were untreated (control, Dulbecco’s modified Eagle’s medium) or treated with 3.3 μM doxorubicin alone, 0.75 U/ml rMETase, alone or their combination. (A) Images of nuclei in HT1080 cells expressing green fluorescent protein (GFP). Scale bars: 100 μm. (B) Quantification of nuclear fragmentation in treated cells. Nuclear fragmentation was observed (arrow heads) with an IX71, fluorescence microscope (Olympus, Tokyo, Japan). *Significantly different at p<0.05 (n=6).

Discussion

We have previously shown that rMETase is synergistic with eribulin (42) and trabectedin (43) on HT-1080 fibrosarcoma.

For patients diagnosed with advanced or metastatic soft-tissue sarcoma, doxorubicin is first-line therapy conferring a median overall survival ranging from 7.7 to 12.8 months (44).

In 1976, Hoffman discovered methionine addiction which is a fundamental hallmark of cancer (45-74). In order to restrict methionine and target methionine addiction, our team developed rMETase (40). Subsequently, it was found that rMETase can be taken orally, which enhances its practicality and safety as a therapeutic option (23, 50).

A large number, of diverse combinations of rMETase and chemotherapy drugs have demonstrated synergy on the major types of cancer (3-33). The current study demonstrates synergy between rMETase and doxorubicin against HT1080 fibrosarcoma cells but not against normal fibroblasts. Cancer cells experience reversible arrest in the late S/G2-phase when methionine levels are depleted (51, 52). Doxorubicin specifically targets the S- phase of the cell cycle and has been shown to act synergistically when combined with methioninase on breast-cancer cells (52, 53). In contrast, the combination of doxorubicin and rMETase did not exhibit synergy in normal Hs27 cells. This is due to the fact that rMETase does not cause late S/G2 cell arrest in normal cells at the IC50 concentration for cancer cells.

Our recent studies demonstrated that the combination of eribulin or trabectedin and rMETase resulted in synergy to reduce cell viability and to cause nuclear fragmentation in dual-color HT1080 cells compared to each drug alone (42, 43). Similar results were observed in the present study with the combination of doxorubicin and rMETase.

Though DR-HT1080 cells were highly resistant to doxorubicin, they were sensitive to rMETase, which along with our previous studies showing rMETase can overcome doxorubicin resistance in various cancers (12, 13, 17, 27, 29, 54), suggest a promising strategy to overcome doxorubicin resistance in the clinic.

In conclusion, the combination of rMETase and doxorubicin and other chemotherapy drugs shows future clinical promise as a therapeutic approach for soft-tissue sarcoma and other cancers (13, 20, 75-79) by specifically targeting an underlying characteristic of cancer, methionine addiction (45-74). Methionine addiction is due to overuse of methionine (46, 48, 55-58, 60, 62, 80, 81) which is made in normal or higher amounts in cancer cells from homocysteine (46-48, 56, 57, 82-84), and is a universal hallmark of cancer (85-87).

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, PhD. 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 HQ provided the methioninase. SM performed the experiments. SM was the major contributor to writing the article and RMH critically revised the article. KM, BMK, MS, MB, NY, KH, HK, SM, KI, TH, HT, and SD critically read the article and made scientific suggestions. All Authors approved the final article.

  • Conflicts of Interest

    The Authors declare no competing interests.

  • Received May 2, 2024.
  • Revision received June 4, 2024.
  • Accepted June 6, 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 Is Selectively Synergistic With Doxorubicin Against Wild-type Fibrosarcoma Cells Compared to Normal Cells and Overcomes Highly-Doxorubicin-resistant Fibrosarcoma
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 Aug 2024, 44 (8) 3261-3268; DOI: 10.21873/anticanres.17144
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