The Effect of Lurbinectedin as a Monotherapy and in Combination with Ionizing Radiation on Sarcoma Cell Lines.

BACKGROUND/OBJECTIVES: Soft tissue sarcomas are rare, heterogeneous tumors with limited therapeutic options and suboptimal outcomes in advanced stages. Lurbinectedin is a promising new antineoplastic alkylating agent. This study investigates its cytotoxic effects and its potential as a radiosensitizing agent on soft tissue sarcoma.

METHODS

Four soft tissue sarcoma cell lines were treated with lurbinectedin alone or in combination with ionizing radiation. Single-dose irradiation in a 4-day protocol was compared with prolonged treatment and an additional fractionated ionizing radiation scheme in a 6-day protocol. Cellular responses were analyzed by flow cytometry for apoptosis (Annexin V)/necrosis (7AAD) and cell cycle (Hoechst), clonogenic cell survival, and scratch assays for cell migration.

RESULTS

In the 4-day protocol, lurbinectedin induced G2/M arrest in all cell lines ( = 0.029) and significantly increased apoptosis/necrosis ( = 0.029) in SW-872. Lurbinectedin-treatment resulted in a decrease ( ≤ 0.002) of clonogenic cells in all cell lines. In the scratch assay, cell migration was delayed in two cell lines ( = 0.048) after lurbinectedin-treatment. Additional radiotherapy had no significant effect compared to lurbinectedin-monotherapy in apoptosis/necrosis and G/2M arrest in the 4-day protocol, clonogenic cell assay, and scratch assay. In the 6-day protocol, lurbinectedin induced an increase ( = 0.029) in G2/M arrest in all cell lines and apoptosis/necrosis in three cell lines, while resulting in a decrease ( < 0.001) of clonogenic cells. Additional radiotherapy had a significant effect on the decrease in clonogenic cells ( ≤ 0.048) in two cell lines but did not increase G2/M arrest and apoptosis/necrosis.

CONCLUSIONS

Lurbinectedin had strong effects on three of the selected cell lines by inducing G2/M arrest, promoting apoptosis/necrosis, and reducing clonogenic survival, suggesting that it may be a promising chemotherapeutic agent in soft tissue sarcoma treatment. The effect on the fourth cell line was limited, as well as the effect on cell migration. Single-dose irradiation occasionally interfered with the effects of Lurbinectedin, whereas adding fractionated irradiation caused an additional decrease in clonogenic survival, indicating that the combination of Lurbinectedin with fractionated ionizing radiation may have promising effects.