HT1080 Fibrosarcoma With Acquired Trabectedin Resistance: Increased Malignancy But Sustained Sensitivity to Methionine Restriction.

BACKGROUND/AIM: Trabectedin is a DNA-binding agent that has shown moderate efficacy for soft-tissue sarcomas. We have previously shown that methionine restriction enhances trabectedin efficacy on both parental and trabectedin-resistant HT1080 (TR-HT1080) cells The aim of the present study was to determine whether fibrosarcoma cells that acquire trabectedin resistance become more malignant but maintain sensitivity to methionine restriction Materials and Methods: TR-HT1080 was established by culturing HT1080 cells in stepwise increasing concentrations of trabectedin. An wound-healing invasion assay was used to compare malignancy of HT1080 and TR-HT1080. , six groups were established: G1-G4 (TR-HT1080): G1, untreated control; G2, trabectedin treatment; G3, methionine-restricted diet; G4, methionine-restricted diet combined with trabectedin; G5, untreated control of parental HT1080; and G6, trabectedin treatment of parental HT1080.

RESULTS

The IC of trabectedin was previously determined to be 3.3 nM for the parental HT1080 cells and 42.9 nM for trabectedin-resistant HT1080 cells, representing a 13-fold increase. Wound-healing invasion assays showed a more rapid wound-closure ratio in TR-HT1080 cells than in parental cells, suggesting increased malignancy compared to the parental cells. The volume of untreated TR-HT1080 tumors grew more rapidly than that of HT1080 tumors, indicating a higher malignancy of TR-HT1080 tumors. The IC of recombinant methioninase was previously determined as 0.75 U/ml for HT1080 and 0.93 U/ml for TR-HT1080 cells. Methionine restriction was highly effective on TR-HT1080 tumors, decreasing tumor growth by 4-fold.

CONCLUSION

TR-HT1080 cells acquired high malignancy by selection for trabectedin resistance. However, methionine restriction overcame trabectedin resistance , strongly inhibiting tumor growth, which should be further investigated in the clinic.