重组甲硫氨酸酶使高度耐埃博利珠单抗的 HT1080 纤维肉瘤细胞对埃博利珠单抗的疗效增加 16 倍，这表明有可能克服软组织肉瘤耐药的临床挑战。

Recombinant Methioninase Increases Eribulin Efficacy 16-fold in Highly Eribulin-resistant HT1080 Fibrosarcoma Cells, Demonstrating Potential to Overcome the Clinical Challenge of Drug-resistant Soft-tissue Sarcoma.

机构信息

AntiCancer Inc., San Diego, CA, U.S.A.

Department of Surgery, University of California, San Diego, CA, U.S.A.

出版信息

Anticancer Res. 2024 Sep;44(9):3777-3783. doi: 10.21873/anticanres.17202.

DOI:10.21873/anticanres.17202

PMID:39197933

Abstract

BACKGROUND/AIM: A major challenge in treating soft-tissue sarcoma is the development of drug resistance. Eribulin, an anti-tubulin agent, is used as a second-line chemotherapy for patients with unresectable or metastatic soft-tissue sarcoma. However, most patients with advanced soft-tissue sarcoma are resistant to eribulin and do not survive. Recombinant methioninase (rMETase) targets the fundamental and general hallmark of cancer, methionine addiction, termed the Hoffman Effect. The present study aimed to show how much rMETase could increase the efficacy of eribulin on eribulin-resistant fibrosarcoma cells in vitro.

MATERIALS AND METHODS

HT1080 human fibrosarcoma cells were exposed to step-wise increasing concentrations of eribulin from 0.15-0.4 nM to establish eribulin-resistant HT1080 (ER-HT1080). ER-HT1080 cells were cultured in vitro and divided into four groups: untreated control; eribulin treated (0.15 nM); rMETase treated (0.75 U/ml); and eribulin (0.15 nM) plus rMETase (0.75 U/ml) treated.

RESULTS

The IC of eribulin on ER-HT1080 cells was 0.95 nM compared to the IC of 0.15 nM on HT1080 cells, a 6-fold increase. The IC of rMETase on ER-HT1080 and HT1080 was 0.87 U/ml and 0.75 U/ml, respectively. The combination of rMETase (0.75 U/ml) and eribulin (0.15 nM) was synergistic on ER-HT1080 cells resulting in an inhibition of 80.1% compared to eribulin alone (5.0%) or rMETase alone (47.1%) (p<0.05). rMETase thus increased the efficacy of eribulin 16-fold on eribulin-resistant fibrosarcoma cells.

CONCLUSION

The present study showed that the combination of eribulin and rMETase can overcome high eribulin resistance of fibrosarcoma. The present results demonstrate that combining rMETase with first- or second-line therapy for soft-tissue sarcoma has the potential to overcome the intractable clinical problem of drug-resistant soft-tissue sarcoma.

摘要

背景/目的：软组织肉瘤治疗的一个主要挑战是耐药性的发展。埃博霉素是一种抗微管药物，被用作无法切除或转移性软组织肉瘤患者的二线化疗药物。然而，大多数晚期软组织肉瘤患者对埃博霉素耐药，无法存活。重组甲硫氨酸酶（rMETase）针对的是癌症的基本和普遍特征，即蛋氨酸成瘾，称为霍夫曼效应。本研究旨在表明 rMETase 可以在多大程度上提高埃博霉素对体外埃博霉素耐药纤维肉瘤细胞的疗效。

材料和方法

将 HT1080 人纤维肉瘤细胞暴露于逐步增加的埃博霉素浓度（0.15-0.4 nM），以建立埃博霉素耐药 HT1080（ER-HT1080）。将 ER-HT1080 细胞在体外培养并分为四组：未处理对照组；埃博霉素处理（0.15 nM）；rMETase 处理（0.75 U/ml）；以及埃博霉素（0.15 nM）加 rMETase（0.75 U/ml）处理。

结果

ER-HT1080 细胞对埃博霉素的 IC 为 0.95 nM，而 HT1080 细胞的 IC 为 0.15 nM，增加了 6 倍。rMETase 对 ER-HT1080 和 HT1080 的 IC 分别为 0.87 U/ml 和 0.75 U/ml。rMETase（0.75 U/ml）与埃博霉素（0.15 nM）联合使用对 ER-HT1080 细胞具有协同作用，抑制率为 80.1%，而单独使用埃博霉素（5.0%）或 rMETase（47.1%）（p<0.05）。因此，rMETase 将埃博霉素对埃博霉素耐药纤维肉瘤细胞的疗效提高了 16 倍。