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Published on: September 8, 2017
Selective Synergy of Recombinant Methioninase Plus Docetaxel Against Docetaxel-resistant and -sensitive Fibrosarcoma
Sei Morinaga1,2,3, Qinghong Han1, Kohei Mizuta1,2
1AntiCancer Inc., San Diego, CA, U.S.A.
Background/Aim:
Docetaxel combined with gemcitabine is a second-line treatment for soft-tissue sarcoma; however, its effectiveness is limited because of docetaxel resistance. The objective of the present study was to determine the potential of recombinant methioninase (rMETase) to enhance the efficacy of docetaxel on high-docetaxel-resistant human fibrosarcoma cells in vitro.
Materials And Methods:
Docetaxel-resistant HT1080 (DTR-HT1080) human fibrosarcoma cells were established by culturing them in by progressively increasing concentrations of docetaxel from 0.02 to 9 nM in vitro. The IC50 values for docetaxel and rMETase, as well as the efficacy of their combination, in inhibiting HT1080 human fibrosarcoma cells, DTR-HT1080 cells, and Hs27 normal human fibroblasts were determined. Four experimental groups were examined in vitro: control group without treatment; docetaxel alone; rMETase alone; docetaxel combined with rMETase.
Results:
The IC50 of docetaxel for DTR-HT1080 cells was 7.57 nM, compared to the parental HT1080 cells with an IC50 of 1.68 nM, a 4.5-fold increase. The IC50 of docetaxel on Hs27 fibroblasts was 4.46 nM. The IC50 of rMETase on HT1080 cells was 0.75 U/ml (data from [6]). The IC50 of rMETase on DTR-HT1080 cells was 0.55 U/ml. The IC50 of rMETase on Hs27 fibroblasts was 0.93 U/ml (data from [6]). Docetaxel (1.68 nM [IC50]) plus rMETase (0.75 U/ml [IC50]) synergistically reduced the viability of HT1080 cells (p<0.05). In contrast, docetaxel (4.46 nM) plus rMETase (0.93 U/ml) did not reduce the viability of Hs27 fibroblasts, compared to either agent alone. The combination of rMETase (0.55 U/ml [IC50]) and docetaxel (1.68 nM [IC50 of the parental cells]) overcame docetaxel resistance of DTR-HT1080 cells, resulting in an inhibition of 48.1% compared to docetaxel alone (6.8%) or rMETase alone (37.5%) (p<0.05). rMETase thus increased the efficacy of docetaxel 7-fold on docetaxel-resistant human fibrosarcoma cells.
Conclusion:
The combination of docetaxel and rMETase was synergistic on HT1080 fibrosarcoma cells, but not normal fibroblasts. rMETase plus docetaxel synergistically reduced the high docetaxel resistance of DTR-HT1080 cells. The present results indicate the clinical potential of rMETase to reduce docetaxel resistance in soft-tissue sarcoma patients in the future.
Insights
Recombinant methioninase (rMETase) combined with docetaxel synergistically overcomes docetaxel resistance in human fibrosarcoma cells. This combination shows potential for treating soft-tissue sarcoma by enhancing docetaxel efficacy.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Docetaxel and gemcitabine are used for soft-tissue sarcoma but face limited efficacy due to docetaxel resistance.
- Developing strategies to overcome docetaxel resistance is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate the potential of recombinant methioninase (rMETase) to enhance docetaxel efficacy.
- To evaluate the synergistic effect of rMETase and docetaxel on docetaxel-resistant human fibrosarcoma cells in vitro.
Main Methods:
- Docetaxel-resistant HT1080 (DTR-HT1080) cells were established in vitro.
- The IC50 values for docetaxel and rMETase were determined for HT1080, DTR-HT1080 cells, and Hs27 normal fibroblasts.
- The efficacy of docetaxel, rMETase, and their combination was assessed in vitro.
Main Results:
- Docetaxel resistance in DTR-HT1080 cells was approximately 4.5-fold higher than in parental HT1080 cells.
- The combination of rMETase and docetaxel demonstrated synergistic effects on HT1080 cells and overcame docetaxel resistance in DTR-HT1080 cells.
- rMETase increased docetaxel's efficacy by 7-fold on docetaxel-resistant cells without affecting normal fibroblasts.
Conclusions:
- The combination of docetaxel and rMETase exhibits synergy against fibrosarcoma cells, including docetaxel-resistant variants.
- rMETase effectively reduces docetaxel resistance in human fibrosarcoma cells.
- This combination holds clinical potential for enhancing docetaxel treatment in soft-tissue sarcoma patients.
