Recombinant Methioninase Is Selectively Synergistic With Doxorubicin Against Wild-type Fibrosarcoma Cells Compared to
Sei Morinaga1,2,3, Qinghong Han1, Kohei Mizuta1,2
1AntiCancer Inc., San Diego, CA, U.S.A.
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.
Insights
Recombinant methioninase (rMETase) combined with doxorubicin shows synergy against fibrosarcoma cells, offering a potential treatment for drug-resistant soft-tissue sarcoma.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Doxorubicin is a primary treatment for soft-tissue sarcoma.
- Acquired resistance to doxorubicin often leads to fatal outcomes.
- Novel therapeutic strategies are needed to overcome doxorubicin resistance.
Purpose of the Study:
- To evaluate the synergistic effect of recombinant methioninase (rMETase) and doxorubicin against fibrosarcoma cells.
- To compare the efficacy of the combination therapy against normal fibroblasts.
- To assess rMETase's effectiveness against doxorubicin-resistant fibrosarcoma cells in vitro.
Main Methods:
- Determined 50% inhibitory concentrations (IC50) for doxorubicin and rMETase, individually and in combination.
- Utilized dual-color cell lines (HT1080) to visualize nuclear fragmentation.
- Observed nuclear fragmentation using fluorescence microscopy.
Main Results:
- The combination of rMETase and doxorubicin demonstrated synergistic effects on fibrosarcoma cells but not normal fibroblasts.
- rMETase alone was effective against both parental and doxorubicin-resistant fibrosarcoma cells.
- Combined treatment induced greater nuclear fragmentation in fibrosarcoma cells compared to single agents.
Conclusions:
- rMETase in combination with doxorubicin holds significant clinical potential for treating fibrosarcoma.
- This combination therapy may be effective against doxorubicin-resistant soft-tissue sarcoma.
- Further clinical investigation of rMETase and doxorubicin combination is warranted.
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