AntiCancer Inc., San Diego, CA, U.S.A.
Department of Surgery, University of California, San Diego, CA, U.S.A.
Anticancer Res. 2024 Sep;44(9):3785-3791. doi: 10.21873/anticanres.17203.
BACKGROUND/AIM: Drug resistance has been a recalcitrant problem for sarcoma patients for many decades. Trabectedin is a second-line chemotherapy for soft-tissue sarcoma that often leads to resistance and death of the patients. The objective of the present study was to address the issue of trabectedin-chemoresistance in HT1080 fibrosarcoma cells by combining recombinant methioninase (rMETase) with trabectedin and examining their efficacy on trabectedin-resistant fibrosarcoma cells in vitro.
Trabectedin-resistant HT1080 (TR-HT1080) cells were generated by subjecting HT1080 human fibrosarcoma cells to increasing trabectedin concentrations (3.3-8 nM). IC values for trabectedin and rMETase were compared for HT1080 and TR-HT1080 cells. TR-HT 1080 cells were placed into four groups to determine synergy of rMETase and trabectedin on TR-HT1080 cells: a control group with no treatment; a group treated with trabectedin (3.3 nM); a group treated with rMETase (0.75 U/ml); and a group treated with both trabectedin (3.3 nM) and rMETase (0.75 U/ml).
The IC value of trabectedin- on TR-HT1080 cells was 42.9 nM, whereas the IC value of trabectedin on the parental HT1080 cells was 3.3 nM, indicating a 13-fold increase. The combination of rMETase (0.75 U/ml) and trabectedin (3.3 nM) was synergistic on TR-HT1080 cells resulting in an inhibition of 64.2% compared to trabectedin alone (5.7%) or rMETase alone (50.5%) (p<0.05). rMETase increased the efficacy of trabectedin 11-fold on trabectedin-resistant fibrosarcoma cells.
The combined administration of trabectedin and rMETase was synergistic on the viability of TR-HT1080 cells in vitro. The combination of rMETase and trabectedin has promising clinical potential for overcoming chemo-resistance of soft-tissue sarcoma.
背景/目的：几十年来，耐药性一直是肉瘤患者面临的一个难题。曲贝替定是软组织肉瘤的二线化疗药物，常导致患者耐药和死亡。本研究旨在通过联合使用重组蛋氨酸酶（rMETase）和曲贝替定来解决 HT1080 纤维肉瘤细胞中的曲贝替定耐药问题，并在体外研究其对曲贝替定耐药纤维肉瘤细胞的疗效。
通过将 HT1080 人纤维肉瘤细胞暴露于逐渐增加的曲贝替定浓度（3.3-8 nM）来生成曲贝替定耐药 HT1080（TR-HT1080）细胞。比较曲贝替定和 rMETase 在 HT1080 和 TR-HT1080 细胞中的 IC 值。将 TR-HT1080 细胞分为四组，以确定 rMETase 和曲贝替定对 TR-HT1080 细胞的协同作用：无治疗的对照组；用曲贝替定（3.3 nM）治疗的组；用 rMETase（0.75 U/ml）治疗的组；用曲贝替定（3.3 nM）和 rMETase（0.75 U/ml）联合治疗的组。
曲贝替定对 TR-HT1080 细胞的 IC 值为 42.9 nM，而曲贝替定对亲本 HT1080 细胞的 IC 值为 3.3 nM，表明耐药性增加了 13 倍。rMETase（0.75 U/ml）与曲贝替定（3.3 nM）联合使用对 TR-HT1080 细胞具有协同作用，与单独使用曲贝替定（5.7%）或单独使用 rMETase（50.5%）相比，抑制率为 64.2%（p<0.05）。rMETase 使曲贝替定对曲贝替定耐药纤维肉瘤细胞的疗效增加了 11 倍。
rMETase 和曲贝替定联合使用对 TR-HT1080 细胞的活力具有协同作用。rMETase 和曲贝替定的联合应用具有克服软组织肉瘤化疗耐药的潜在临床应用前景。
