HT1080 Human Fibrosarcoma Cells Selected for Super-eribulin Resistance In Vitro Become More Malignant and Are Arrested Synergistically by Methionine Restriction in Combination With Eribulin in Nude Mice.

Abstract

Background/aim: Eribulin is a microtubule inhibitor used in the treatment of various malignancies, including soft-tissue sarcoma. However, the development of eribulin resistance is a recalcitrant clinical problem. The present study demonstrates that super eribulin-resistant HT1080 human fibrosarcoma cells become highly malignant but can be eradicated synergistically by the combination of eribulin and methionine restriction in nude mice.

Materials and methods: The cell viability of parental HT1080 cells and super eribulin-resistant HT1080 was determined following eribulin treatment using the WST-8 reagent. In vitro invasion assays, comprising wound-healing of cell monolayers, were performed to determine the degree of malignancy. Tumor growth to determine malignancy and tumor-growth sensitivity to eribulin, or a methionine-restricted diet, or their combination were analyzed in athymic nude mice.

Results: The IC₅₀ of eribulin for parental HT1080 cells was 0.15 nM, whereas for super eribulin-resistant HT1080 cells, the IC₅₀ of eribulin was 18 nM, a 120-fold increase. Super eribulin-resistant HT1080 cells had a more rapid wound-healing closure rate in vitro than their parental HT1080 cells, indicating increased malignancy. Similarly, in vivo, untreated super eribulin-resistant HT1080 tumors grew faster than parental HT1080 tumors, confirming their high malignancy. The combination of a methionine-restricted diet and eribulin synergistically arrested super eribulin-resistant HT1080 tumors. Methionine restriction sensitized these highly resistant and malignant cells to eribulin.

Conclusion: Methionine restriction combined with eribulin represents a promising strategy to effectively treat eribulin-resistant high-malignancy fibrosarcoma, that can be immediately applied to the clinic.